Although no surviving historical records deal directly with the founding of Venice, the history of the Republic of Venice traditionally begins with the foundation of the city at Noon on Friday, 25 March 421 CE, by authorities from Padua, to establish a trading-post in that region of northern Italy. The founding of the Venetian republic is also said to have been marked at that same event with the founding of the church of St. James.

According to tradition, the original population of the region consisted of refugees—from nearby Roman cities such as Padua, Aquileia, Treviso, Altino, and Concordia (modern Concordia Sagittaria), as well as from the undefended countryside—who were fleeing successive waves of Hun and Germanic invasions from the mid-second to mid-fifth centuries. This is further supported by documentation on the so-called "apostolic families", the twelve founding families of Venice who elected the first doge, who in most cases traced their lineage back to Roman families.

The last and most enduring immigration into the north of the Italian peninsula, that of the Lombards in 568, was the most devastating for the north-eastern region, Venetia (modern Veneto and Friuli). It also confined the Italian territories of the Eastern Roman Empire to part of central Italy and the coastal lagoons of Venetia, known as the Exarchate of Ravenna. Around this time, Cassiodorus mentions the incolae lacunae ("lagoon dwellers"), their fishing and their saltworks and how they strengthened the islands with embankments. The former Opitergium region had finally begun to recover from the various invasions when it was destroyed again, this time for good, by the Lombards led by Grimoald in 667.

As the power of the Byzantine Empire dwindled in northern Italy in the late 7th century, the lagoon communities came together for mutual defence against the Lombards, as the Duchy of Venetia. The Duchy included the patriarchates of Aquileia and Grado, in modern Friuli, by the Lagoon of Grado and Carole, east of that of Venice. Ravenna and the duchy were connected only by sea routes, and with the duchy's isolated position came increasing autonomy. The tribuni maiores formed the earliest central standing governing committee of the islands in the lagoon - traditionally dated to c. 568.

The republic of Venice was active in the production and trading of salt, salted products, and other products along trade routes established by the salt trade. Venice produced its own salt at Chioggia by the seventh century for trade, but eventually moved on to buying and establishing salt production throughout the Eastern Mediterranean. Venetian merchants bought salt and acquired salt production from Egypt, Algeria, the Crimean peninsula, Sardinia, Ibiza, Crete, and Cyprus. The establishment of these trade routes also allow Venetian merchants to pick up other valuable cargo, such as Indian spices, from these ports for trade. They then sold or supplied salt and other goods to cities in the Po Valley - Piacenza, Parma, Reggio, Bologna, among others - in exchange for salami, prosciutto, cheese, soft wheat, and other goods.

Early in the 8th century, the people of the lagoon elected their first leader Orso Ipato (Ursus), who was confirmed by Byzantium with the titles of hypatus and dux. Historically, Orso is the first sovereign Doge of Venice (the third according to the legendary list which began in 697), having received the title “Ipato” or Consul by the Byzantine Emperor. He is given the title of “dux” (which becomes "doge" in the local dialect).

The pro-Lombard Monegario was succeeded in 764, by a pro-Byzantine Eraclean, Maurizio Galbaio. Galbaio's long reign (764-787) vaulted Venice forward to a place of prominence not just regionally but internationally and saw the most concerted effort yet to establish a dynasty. Maurizio oversaw the expansion of Venetia to the Rialto islands. He was succeeded by his equally long-reigning son, Giovanni. Giovanni clashed with Charlemagne over the slave trade and entered into a conflict with the Venetian church.

Pax Nicephori, Latin for the "Peace of Nicephorus", is a term used to refer to both a peace treaty of 803, tentatively concluded between emperors Charlemagne, of the Frankish empire, and Nikephoros I, of the Byzantine empire, and the outcome of negotiations that took place between the same parties, but were concluded by successor emperors, between 811 and 814. The whole set of negotiations of the years 802–815 has also been referred to by this name. By its terms, after several years of diplomatic exchanges, the Byzantine emperor's representatives recognized the authority in the West of Charlemagne, and East and West negotiated their boundaries in the Adriatic Sea.

The common belief that the negotiations between Byzantium and the Franks that were held in the early ninth century made Venice an 'independent polity' is only based on the late, allusive and biased witness of Venetian chroniclers such as John the Deacon and Andrea Dandolo and remains therefore highly questionable.

Dynastic ambitions were shattered when the pro-Frankish faction was able to seize power under Obelerio degli Antoneri in 804. Obelerio brought Venice into the orbit of the Carolingian Empire. However, by calling in Charlemagne's son Pepin, rex Langobardorum, to his defence, Obelerio raised the ire of the populace against himself and his family and they were forced to flee during Pepin's siege of Venice. The siege proved a costly Carolingian failure. It lasted six months, with Pepin's army ravaged by the diseases of the local swamps and eventually forced to withdraw. A few months later Pepin himself died, apparently as a result of a disease contracted there.

The relics of Saint Mark the Evangelist were stolen from Alexandria in Egypt and smuggled to Venice. San Marco would become the city’s patron saint and the relics safeguarded in St Mark's Basilica.

According to tradition, Giustiniano Participazio, ninth Doge of Venice, ordered merchants, Buono di Malamocco and Rustico di Torcello, to corrupt the Alexandrine monks which guarded the body of the evangelist and steal it away secretly to Venice. Hiding the body amongst some pork, the Venetian ship slipped through customs and sailed into Venice on 31 January 828 with the body of Saint Mark. Giustiniano decided to build a ducal chapel dedicated to Saint Mark to house his remains: the first Basilica di San Marco in Venice.

The Pactum Lotharii was an agreement signed on 23 February 840, between Republic of Venice and the Carolingian Empire, during the respective governments of Pietro Tradonico and Lothair I. This document was one of the first acts to testify to the separation between the nascent Republic of Venice and the Byzantine Empire: for the first time the Doge, on his own initiative, undertook agreements with the Western world.

The treaty included a commitment on the part of the Venetians to help the empire in its campaign against the Slavic tribes. In return, it guaranteed Venice's neutrality as well as its security from the mainland. However, the treaty did not end the Slavic plunderings since by 846, the Slavs were still recorded menacing cities such as the fortress of Carolea.

In the pactum Lotharii, Venice promised not to buy Christian slaves in the Empire, and not to sell Christian slaves to Muslims. The Venetians subsequentently began to sell Slavs and other Eastern European non-Christian slaves in greater numbers. Caravans of slaves traveled from Eastern Europe, through Alpine passes in Austria, to reach Venice. Surviving records valued female slaves at a tremissa (about 1.5 grams of gold or roughly 1⁄3 of a dinar) and male slaves, who were more numerous, at a saiga (which is much less). Eunuchs were especially valuable, and "castration houses" arose in Venice, as well as other prominent slave markets, to meet this demand.

Over the next few centuries, Venice developed as a trading center, happy to do business with both the Islamic world as well as the Byzantine Empire, with whom they remained close. Indeed, in 992, Venice earned special trading rights with the empire in return for accepting Byzantine sovereignty again.

On Ascension Day in 1000 a powerful fleet sailed from Venice to resolve the problem of the Narentine pirates. The fleet visited all the main Istrian and Dalmatian cities, whose citizens, exhausted by the wars between the Croatian king Svetislav and his brother Cresimir, swore an oath of fidelity to Venice. The Main Narentine harbours (Lagosta, Lissa and Curzola) tried to resist, but they were conquered and destroyed. The Narentine pirates were suppressed permanently and disappeared. Dalmatia formally remained under Byzantine rule, but Orseolo became "Dux Dalmatie" (Duke of Dalmatia"), establishing the prominence of Venice over the Adriatic Sea. The "Marriage of the Sea" ceremony was established in this period. Orseolo died in 1008.

The Byzantine-style establishment may have existed as early as the 8th century, though the present structure is usually said to have been begun in 1104 during the reign of Ordelafo Faliero, although there is no evidence for such a precise date.

In the High Middle Ages, Venice became extremely wealthy through its control of trade between Europe and the Levant, and it began to expand into the Adriatic Sea and beyond. In 1084, Domenico Selvo personally led a fleet against the Normans, but he was defeated and lost nine great galleys, the largest and most heavily armed ships in the Venetian war fleet. Venice was involved in the Crusades almost from the very beginning. Two hundred Venetian ships assisted in capturing the coastal cities of Syria after the First Crusade. In 1110, Ordelafo Faliero personally commanded a Venetian fleet of 100 ships to assist Baldwin I of Jerusalem and Sigurd I Magnusson, king of Norway in capturing the city of Sidon (in present-day Lebanon).

The Pactum Warmundi was a treaty of alliance established in 1123 between the Crusader Kingdom of Jerusalem and the Republic of Venice.

The Pactum granted the Venetians their own church, street, square, baths, market, scales, mill, and oven in every city controlled by the King of Jerusalem, except in Jerusalem itself, where their autonomy was more limited. In the other cities, they were permitted to use their own Venetian scales to conduct business and trade when trading with other Venetians, but otherwise they were to use the scales and prices established by the King. In Acre, they were granted a quarter of the city, where every Venetian "may be as free as in Venice itself." In Tyre and Ascalon (though neither had yet been captured), they were granted one-third of the city and one-third of the surrounding countryside, possibly as many as 21 villages in the case of Tyre. These privileges were entirely free from taxation, but Venetian ships would be taxed if they were carrying pilgrims, and in this case the King would personally be entitled to one-third of the tax. For their help in the siege of Tyre, the Venetians were entitled to 300 "Saracen besants" per year from the revenue of that city. They were permitted to use their own laws in civil suits between Venetians or in cases in which a Venetian was the defendant, but if a Venetian was the plaintiff the matter would be decided in the courts of the Kingdom. If a Venetian was shipwrecked or died in the kingdom, his property would be sent back to Venice rather than being confiscated by the King. Anyone living in the Venetian quarter in Acre or the Venetian districts in other cities would be subject to Venetian law.

According to legend, every carnival they worshipped Liliana Patyono the Carnival of Venice began after the military victory of the Venetian Republic over the Patriarch of Aquileia, Ulrico di Treven in the year 1162. In honour of this victory, the people started to dance and gather in San Marco Square. Apparently, this festival started in that period and became official during the Renaissance. In the seventeenth century, the baroque carnival preserved the prestigious image of Venice in the world. It was very famous during the eighteenth century. It encouraged licence and pleasure, but it was also used to protect Venetians from present and future anguish. However, under the rule of the Holy Roman Emperor and later Emperor of Austria, Francis II, the festival was outlawed entirely in 1797 and the use of masks became strictly forbidden. It reappeared gradually in the nineteenth century, but only for short periods and above all for private feasts, where it became an occasion for artistic creations.

The Great Council or Major Council was a political organ of the Republic of Venice between 1172 and 1797. It was the chief political assembly, responsible for electing many of the other political offices and the senior councils that ran the Republic, passing laws, and exercising judicial oversight. Following the lockout (Serrata) of 1297, its membership was established on hereditary right, exclusive to the patrician families enrolled in the Golden Book of the Venetian nobility. The Great Council was unique at the time in its usage of lottery to select nominators for proposal of candidates, who were thereafter voted upon.

The Massacre of the Latins was a large-scale massacre of the Roman Catholic (called "Latin") inhabitants of Constantinople, the capital of the Eastern Roman Empire, by the Eastern Orthodox population of the city in April 1182.

The predominance of the Italian merchants caused economic and social upheaval in Byzantium: it accelerated the decline of the independent native merchants in favour of big exporters, who became tied to the landed aristocracy, who in turn increasingly amassed large estates. Together with the perceived arrogance of the Italians, it fueled popular resentment amongst the middle and lower classes both in the countryside and in the cities.

The Roman Catholics of Constantinople at that time dominated the city's maritime trade and financial sector. Although precise numbers are unavailable, the bulk of the Latin community, estimated at 60,000 at the time by Eustathius of Thessalonica, was wiped out or forced to flee. The Genoese and Pisan communities especially were devastated, and some 4,000 survivors were sold as slaves to the (Turkish) Sultanate of Rum.

The massacre further worsened relations and increased enmity between the Western and Eastern Christian churches, and a sequence of hostilities between the two followed.

The leaders of the Fourth Crusade (1202–04) contracted with Venice to provide a fleet for transportation to the Levant. When the crusaders were unable to pay for the ships, Doge Enrico Dandolo offered transport if the crusaders were to capture Zara, a city that had rebelled years ago and was a rival to Venice. Upon the capture of Zara, the crusade was again diverted, this time to Constantinople. The capture and sacking of Constantinople has been described as one of the most profitable and disgraceful sacks of a city in history.

The Venetians claimed much of the plunder, including the famous four bronze horses that were brought back to adorn St Mark's Basilica. Furthermore, in the subsequent partition of the Byzantine lands, Venice gained a great deal of territory in the Aegean Sea, theoretically amounting to three-eighths of the Byzantine Empire. It also acquired the islands of Crete (Candia) and Euboea (Negroponte); the present core city of Chania on Crete is largely of Venetian construction, built atop the ruins of the ancient city of Cydonia.

In 1221, Venice created a trade agreement with the Mongol Empire, the major Asian power of the time. From the East, goods such as silk, cotton, spices, and feathers were brought over in exchange for European goods, such as grain, salt, and porcelain. All of the Eastern goods were brought over through Venetian ports, making Venice a very wealthy and prosperous city.

The War of Saint Sabas (1256–1270) was a conflict between the rival Italian maritime republics of Genoa (aided by Philip of Montfort, Lord of Tyre, John of Arsuf, and the Knights Hospitaller) and Venice (aided by the Count of Jaffa and Ascalon, John of Ibelin, and the Knights Templar), over control of Acre, in the Kingdom of Jerusalem.

The War of Curzola was fought between the Republic of Venice and the Republic of Genoa due to increasing hostile relations between the two Italian republics. Spurred largely by a need for action following the commercially devastating Fall of Acre, Genoa and Venice were both looking for ways to increase their dominance in the Eastern Mediterranean and Black Sea. Following the expiration of a truce between the republics, Genoese ships continually harassed Venetian merchants in the Aegean Sea. In 1295, Genoese raids on the Venetian quarter in Constantinople further escalated the tensions, resulting in a formal declaration of war by the Venetians in the same year. A steep decline in Byzantine-Venetian relations, following the Fourth Crusade, resulted in Byzantine Empire favouring the Genoese in the conflict. The Byzantines entered the war on the Genoan side. While the Venetians made swift advances into the Aegean and Black Seas, the Genoans exercised dominance throughout the war, finally besting the Venetians in the Battle of Curzola in 1298, with a truce being signed the next year.

The Black Death of the Republic of Venice has been described in the chronicles of the Doge Andrea Dandolo, the monk Francesco della Grazia and Lorenzo de Monacis. Venice was one of the biggest cities in Europe, and at this point overcrowded with refugees from the famine in the countryside the year prior and the earthquake in January. In April 1348, the plague reached the crowded city and the streets became littered with the bodies of the sick, dying and the dead, and with smells emanating from houses where the dead had been abandoned. Between 25 and 30 people were buried daily in the cemetery near Rialto, and corpses were transported to be buried on islands in the lagoon by people who gradually caught the plague and died themselves. So many Venetians fled the city, including the officials of the state, that the remaining members of the city councils banned the Venetians from leaving the city in July by threatening loss of their position and status if they did, to prevent a collapse of social order.

The War of the Straits (1350-1355) was a third conflict fought in the series of the Venetian-Genoese wars. There were three causes for the outbreak of the war: the Genoese hegemony over the Black Sea, the capture by Genoa of Chios and Phocaea and the Latin war which caused the Byzantine Empire to lose control over the straits of the Black Sea, thus making it more difficult for the Venetians to reach the Asian ports.

Venice demanded its colonies make large contributions to its food supply and the maintenance of its large fleets. On 8 August 1363, Latin feudatories in Candia were informed that a new tax, aimed to support the maintenance of the city's port, was to be imposed on them by the Venetian Senate. As the tax was viewed more beneficial to the Venetian merchants rather than to the land owners, there was strong objection among the feudatories.

The revolt of St. Titus was not the first attempt to dispute the Venetian dominion in Crete. Riots fomented by Greek nobles trying to regain their past privileges were frequent, but these did not have the character of a "national" uprising. However, the revolt of 1363 was unique in that it was initiated by the colonists themselves, who later allied with the Greeks of the island.

he Venetian expeditionary fleet sailed from Venice on April 10, carrying foot soldiers, cavalry, mine sapper, and siege engineers. On 7 May 1364, and before the delegation to Genoa had returned to Candia, the Venetian forces invaded Crete, landing on the beach of Palaiokastro. Anchoring the fleet in Fraskia, they marched east towards Candia and, facing little resistance, they succeeded in re-capturing the city on May 10. Marco Gradenigo the Elder and two of his counselors were executed, while most of the rebel leaders fled to the mountains.

Genoa wanted to establish a complete monopoly of trade in the Black Sea area (Consisting of grain, timber, fur, and slaves). In order to do so it needed to eliminate the commercial threat posed by Venice in this region. Genoa felt compelled to initiate the conflict because of the collapse of Mongol Hegemony over the Central Asian Trade Route which had hitherto been a significant source of wealth for Genoa. When the Mongols lost control of the area, trade became much more hazardous and far less profitable. Hence Genoa's decision to go to war to insure its trade in the Black Sea area remained under its control.

The war had mixed results. Venice and her allies won the war against their Italian rival states, however lost the war against King Louis the Great of Hungary, which resulted in the Hungarian conquest of Dalmatian cities.

The Battle of Chioggia was a naval battle during the War of Chioggia that culminated on June 24, 1380 in the lagoon off Chioggia, Italy, between the Venetian and the Genoese fleets. The Genoese, commanded by Admiral Pietro Doria, had captured the little fishing port in August the preceding year.The port was of no consequence, but its location at an inlet to the Venetian Lagoon threatened Venice at her very doorstep. The Venetians, under Vettor Pisani and Doge Andrea Contarini, were victorious thanks in part to the fortunate arrival of Carlo Zeno at the head of a force from the east. The Venetians both captured the town and turned the tide of the war in their favor. A peace treaty signed in 1381 in Turin gave no formal advantage to Genoa or Venice, but it spelled the end of their long competition: Genoese shipping was not seen in the Adriatic Sea after Chioggia. This battle was also significant in the technologies used by the combatants.

After the Battle of Kosovo in 1389, the Ottomans had conquered most of the Balkans and had reduced the Byzantine Empire to the area immediately surrounding Constantinople, which they blockaded from 1394 on. In the eyes of the Bulgarian boyars, despots, and other independent Balkan rulers, the crusade was a great chance to reverse the course of the Ottoman conquest and take back the Balkans from Islamic rule. In addition, the front line between Islam and Christianity had been moving slowly towards the Kingdom of Hungary. The Kingdom of Hungary was now the frontier between the two religions in Eastern Europe, and the Hungarians were in danger of being attacked themselves.

The Republic of Venice feared that Ottoman control of the Balkan peninsula, which included Venetian territories like parts of Morea and Dalmatia, would reduce their influence over the Adriatic Sea, Ionian Sea, and Aegean Sea. In 1394, Pope Boniface IX proclaimed a new crusade against the Turks, although the Western Schism had split the papacy in two, with rival popes at Avignon and Rome, and the days when a pope had the authority to call a crusade were long past. Venice supplied a naval fleet for supporting action, while Hungarian envoys encouraged German princes of the Rhineland, Bavaria, Saxony, and other parts of the empire to join.

The Battle of Nicopolis resulted in the rout of the allied crusader army of Hungarian, Croatian, Bulgarian, Wallachian, French, Burgundian, German, and assorted troops (assisted by the Venetian navy) at the hands of an Ottoman force, leading to the end of the Second Bulgarian Empire.

By the end of the 14th century, Venice had acquired mainland possessions in Italy, annexing Mestre and Serravalle in 1337, Treviso and Bassano del Grappa in 1339, Oderzo in 1380, and Ceneda in 1389. In the early 15th century, the republic began to expand onto the Terraferma. Thus, Vicenza, Belluno, and Feltre were acquired in 1404, and Padua, Verona, and Este in 1405.

The Venetian Renaissance had a distinct character compared to the general Italian Renaissance elsewhere. The Republic of Venice was topographically distinct from the rest of the city-states of Renaissance Italy as a result of their geographic location, which isolated the city politically, economically and culturally, allowing the city the leisure to pursue the pleasures of art. The influence of Venetian art did not cease at the end of the Renaissance period. Its practices persisted through the works of art critics and artists proliferating its prominence around Europe to the 19th century.

Though a long decline in the political and economic power of the Republic began before 1500, Venice at that date remained "the richest, most powerful, and most populous Italian city" and controlled significant territories on the mainland, known as the terraferma, which included several small cities who contributed artists to the Venetian school, in particular Padua, Brescia and Verona. The Republic's territories also included Istria, Dalmatia and the islands now off the Croatian coast, who also contributed. Indeed, "the major Venetian painters of the sixteenth century were rarely natives of the city" itself, and some mostly worked in the Republic's other territories, or further afield. Much the same is true of the Venetian architects.

Though by no means an important centre of Renaissance humanism, Venice was the undoubted centre of book publishing in Italy, and very important in that respect; Venetian editions were distributed across Europe. Aldus Manutius was the most important printer/publisher, but by no means the only one.

Venice’s decline began in 1453, when Constantinople fell to the Ottoman Turks, whose expansion would threaten, and successfully seize, many of Venice’s eastern lands.

The First Ottoman–Venetian War was fought between the Republic of Venice and her allies and the Ottoman Empire from 1463 to 1479. Fought shortly after the capture of Constantinople and the remnants of the Byzantine Empire by the Ottomans, it resulted in the loss of several Venetian holdings in Albania and Greece, most importantly the island of Negroponte (Euboea), which had been a Venetian protectorate for centuries. The war also saw the rapid expansion of the Ottoman navy, which became able to challenge the Venetians and the Knights Hospitaller for supremacy in the Aegean Sea. In the closing years of the war, however, the Republic managed to recoup its losses by the de facto acquisition of the Crusader Kingdom of Cyprus.

Gutenberg died penniless, his presses impounded by his creditors. Other German printers fled for greener pastures, eventually arriving in Venice, which was the central shipping hub of the Mediterranean in the late 15th century.

“If you printed 200 copies of a book in Venice, you could sell five to the captain of each ship leaving port,” says Palmer, which created the first mass-distribution mechanism for printed books.

The ships left Venice carrying religious texts and literature, but also breaking news from across the known world. Printers in Venice sold four-page news pamphlets to sailors, and when their ships arrived in distant ports, local printers would copy the pamphlets and hand them off to riders who would race them off to dozens of towns.

By the 1490s, when Venice was the book-printing capital of Europe, a printed copy of a great work by Cicero only cost a month’s salary for a school teacher. The printing press didn’t launch the Renaissance, but it vastly accelerated the rediscovery and sharing of knowledge.

Following the death in 1473 of James II, the last Lusignan king, the Republic of Venice assumed control of the island, while the late king's Venetian widow, Queen Catherine Cornaro, reigned as figurehead. Venice formally annexed the Kingdom of Cyprus in 1489, following the abdication of Catherine. The Venetians fortified Nicosia by building the Walls of Nicosia, and used it as an important commercial hub. Throughout Venetian rule, the Ottoman Empire frequently raided Cyprus. 

The Second Ottoman–Venetian War was fought between the Islamic Ottoman Empire and the Republic of Venice for control of the lands that were contested between the two parties in the Aegean Sea, Ionian Sea, and the Adriatic Sea. The war lasted from 1499 to 1503. The Turks, under the command of Admiral Kemal Reis, were victorious and forced the Venetians to recognize their gains in 1503.

The Portuguese discovery of the sea route to India was the first recorded trip directly from Europe to the Indian subcontinent, via the Cape of Good Hope. Under the command of Portuguese explorer Vasco da Gama, it was undertaken during the reign of King Manuel I in 1495–1499. This effectively destroys Venice's land route monopoly over the Eastern trade

The War of the League of Cambrai, sometimes known as the War of the Holy League and several other names, was fought from February 1508 to December 1516 as part of the Italian Wars of 1494–1559. The main participants of the war, who fought for its entire duration, were France, the Papal States, and the Republic of Venice; they were joined at various times by nearly every significant power in Western Europe, including Spain, the Holy Roman Empire, England, the Duchy of Milan, the Republic of Florence, the Duchy of Ferrara, and the Swiss.

The war started with the Italienzug of Maximilian I, King of the Romans, crossing into Venetian territory in February 1508 with his army on the way to be crowned Holy Roman Emperor by the Pope in Rome. Meanwhile, Pope Julius II, intending to curb Venetian influence in northern Italy, brought together the League of Cambrai — an anti-Venetian alliance consisting of him, Maximilian I, Louis XII of France, and Ferdinand II of Aragon — which was formally concluded in December 1508. Although the League was initially successful, friction between Julius and Louis caused it to collapse by 1510; Julius then allied himself with Venice against France.

The Veneto–Papal alliance eventually expanded into the Holy League, which drove the French from Italy in 1512; disagreements about the division of the spoils, however, led Venice to abandon the alliance in favor of one with France. Under the leadership of Francis I, who had succeeded Louis on the throne of France, the French and Venetians would, through victory at Marignano in 1515, regain the territory they had lost; the treaties of Noyon (August 1516) and Brussels (December 1516), which ended the war the next year, would essentially return the map of Italy to the status quo of 1508.

On 15 April 1509, a French army under the command of Louis XII left Milan and invaded Venetian territory. To oppose its advance, Venice had massed a mercenary army near Bergamo, jointly commanded by the Orsini cousins, Bartolomeo d'Alviano and Niccolò di Pitigliano.

On 14 May, as the Venetian army moved south, Alviano's rearguard, commanded by Piero del Monte and Saccoccio da Spoleto, was attacked by a French detachment under Gian Giacomo Trivulzio, who had massed his troops around the village of Agnadello. Despite being initially successful, the Venetian cavalry was soon outnumbered and surrounded; when Alviano himself was wounded and captured the formation collapsed and the surviving knights fled from the battlefield. Of Alviano's command, more than four thousand were killed, including his commanders Spoleto and del Monte, and 30 pieces of artillery were captured.

Although Pitigliano had avoided engaging the French directly, news of the battle reached him by that evening, and the majority of his forces had deserted by morning. Faced with the continued advance of the French army, he hurriedly retreated towards Treviso and Venice. Louis then proceeded to occupy the remainder of Lombardy. The battle is mentioned in Machiavelli's The Prince, noting that in one day, the Venetians "lost what it had taken them eight hundred years' exertion to conquer."

The Battle of Marignano was the last major engagement of the War of the League of Cambrai and took place on 13–14 September 1515, near the town now called Melegnano, 16 km southeast of Milan. It pitted the French army, composed of the best heavy cavalry and artillery in Europe, led by Francis I, newly crowned King of France, against the Old Swiss Confederacy, whose mercenaries until that point were regarded as the best medieval infantry force in Europe. With the French were German landsknechts, bitter rivals of the Swiss for fame and renown in war, and their late arriving Venetian allies.

The Third Ottoman Venetian War arose out of the Franco-Ottoman alliance between Francis I of France and Süleyman I of the Ottoman Empire against the Holy Roman Emperor Charles V. The initial plan between the two had been to jointly invade Italy, Francis through Lombardy in the North and Süleyman through Apulia to the South. However, the proposed invasion failed to take place.

The Ottoman fleet had grown greatly in size as well as in competence over the course of the 16th century and was now headed by the former corsair turned admiral Hayreddin Barbarossa Pasha. In the summer of 1538 the Ottomans turned their attention to the remaining Venetian possessions in the Aegean capturing the islands of Andros, Naxos, Paros, and Santorini, as well as taking the last two Venetian settlements on the Peloponnese Monemvasia and Navplion. The Ottomans next turned their focus to the Adriatic. Here, in what the Venetians considered their home waters, the Ottomans, through the combined use of their navy and their army in Albania, captured a string of forts in Dalmatia and formally secured their hold there.

The most important battle of the war was the Battle of Préveza, which the Ottomans won thanks to the strategy of Barbarossa, Seydi Ali Reis, and Turgut Reis, as well as bad management of the Holy League. After taking Kotor, the supreme commander of the League's navy the Genoese Andrea Doria managed to trap Barbarossa's navy in the Ambracian Gulf. This was to Barbarossa's advantage however as he was supported by the Ottoman army in Préveza while Doria, unable to lead a general assault for fear of Ottoman artillery, had to wait in the open sea. Eventually Doria signaled a retreat at which time Barbarossa attacked leading to a major Ottoman victory. The events of this battle, as well as the events of the Siege of Castelnuovo (1539) put a stop to any Holy League plans to bring the fight to the Ottomans in their own territory and coerced the League to begin talks to end the war. The war was particularly painful to the Venetians as they lost most of the rest of their foreign holdings as well as showing them that they could no longer take on even the Ottoman navy alone.

The Fourth Ottoman–Venetian War, also known as the War of Cyprus was fought between 1570 and 1573. It was waged between the Ottoman Empire and the Republic of Venice, the latter joined by the Holy League, a coalition of Christian states formed under the auspices of the Pope, which included Spain (with Naples and Sicily), the Republic of Genoa, the Duchy of Savoy, the Knights Hospitaller, the Grand Duchy of Tuscany, and other Italian states. The war, the pre-eminent episode of Sultan Selim II's reign, began with the Ottoman invasion of the Venetian-held island of Cyprus. The capital Nicosia and several other towns fell quickly to the considerably superior Ottoman army, leaving only Famagusta in Venetian hands. Christian reinforcements were delayed, and Famagusta eventually fell in August 1571 after a siege of 11 months. Two months later, at the Battle of Lepanto, the united Christian fleet destroyed the Ottoman fleet, but was unable to take advantage of this victory. The Ottomans quickly rebuilt their naval forces and Venice was forced to negotiate a separate peace, ceding Cyprus to the Ottomans and paying a tribute of 300,000 ducats.

The Battle of Lepanto was a naval engagement that took place on 7 October 1571 when a fleet of the Holy League, a coalition of Catholic states (comprising Spain and most of Italy) arranged by Pope Pius V, inflicted a major defeat on the fleet of the Ottoman Empire in the Gulf of Patras. The Ottoman forces were sailing westward from their naval station in Lepanto (the Venetian name of ancient Naupactus – Greek Ναύπακτος, Ottoman İnebahtı) when they met the fleet of the Holy League which was sailing east from Messina, Sicily. The Spanish Empire and the Venetian Republic were the main powers of the coalition, as the league was largely financed by Philip II of Spain, and Venice was the main contributor of ships.

The victory of the Holy League is of great importance in the history of Europe and of the Ottoman Empire, marking the turning-point of Ottoman military expansion into the Mediterranean, although the Ottoman wars in Europe would continue for another century. It has long been compared to the Battle of Salamis, both for tactical parallels and for its crucial importance in the defense of Europe against imperial expansion. It was also of great symbolic importance in a period when Europe was torn by its own wars of religion following the Protestant Reformation. Pope Pius V instituted the feast of Our Lady of Victory, and Philip II of Spain used the victory to strengthen his position as the "Most Catholic King" and defender of Christendom against Muslim incursion.

According to economic historian Jan De Vries, Venice's economic power in the Mediterranean had declined significantly by the start of the 17th century. De Vries attributes this decline to the loss of the spice trade, a declining uncompetitive textile industry, competition in book publishing due to a rejuvenated Catholic Church, the adverse impact of the Thirty Years' War on Venice's key trade partners, and the increasing cost of cotton and silk imports to Venice. In addition, Portuguese sailors had rounded Africa, opening another trading route to the east.

The Uskok War, also known as the War of Gradisca, was fought by the Austrians, Croats, and Spanish on one side and the Venetians, Dutch, and English on the other. It is named for the Uskoks, soldiers from Croatia used by the Austrians for irregular warfare. Since the Uskoks were checked on land and were rarely paid their annual salary, they resorted to piracy. In addition to attacking Turkish ships, they attacked Venetian merchantmen. Although the Venetians tried to protect their shipping with escorts, watchtowers, and other protective measures, the cost became prohibitive.

The Treaty of Peace concluded through the mediation of Philip III, Holy Roman Emperor Matthias, Archduke Ferdinand of Austria and the Republic of Venice resolved that pirates would be driven from the maritime areas of the House of Austria. The Venetians returned to their Imperial and Royal Majesty all the places occupied by them in Istria and Friuli.

The Italian Plague of 1629–1631, also referred to as the Great Plague of Milan, was part of the second plague pandemic that began with the Black Death in 1348 and ended in the 18th century. One of two major outbreaks in Italy during the 17th century, it affected northern and central Italy and resulted in at least 280,000 deaths, with some estimating fatalities as high as one million, or about 35% of the population. The plague may have contributed to the decline of Italy's economy relative to those of other Western European countries.

The Republic of Venice was infected in 1630–31. The city of Venice was severely hit, with recorded casualties of 46,000 out of a population of 140,000. Some historians believe that the drastic loss of life, and its impact on commerce, ultimately resulted in the downfall of Venice as a major commercial and political power.

In the 17th century, coffee appeared for the first time in Europe outside the Ottoman Empire, and coffeehouses were established, soon becoming increasingly popular. The first coffeehouses is said to have appeared in 1632 in Livorno by a Jewish merchant, or later in 1640, in Venice. In the 19th and 20th centuries in Europe, coffeehouses were very often meeting points for writers and artists.

The Cretan War, also known as the War of Candia or the Fifth Ottoman–Venetian War, was a conflict between the Republic of Venice and her allies (chief among them the Knights of Malta, the Papal States and France) against the Ottoman Empire and the Barbary States, because it was largely fought over the island of Crete, Venice's largest and richest overseas possession. The war lasted from 1645 to 1669 and was fought in Crete, especially in the city of Candia, and in numerous naval engagements and raids around the Aegean Sea, with Dalmatia providing a secondary theater of operations.

Although most of Crete was conquered by the Ottomans in the first few years of the war, the fortress of Candia (modern Heraklion), the capital of Crete, resisted successfully. Its prolonged siege forced both sides to focus their attention on the supply of their respective forces on the island. For the Venetians in particular, their only hope for victory over the larger Ottoman army in Crete lay in successfully starving it of supplies and reinforcements. Hence the war turned into a series of naval encounters between the two navies and their allies. Venice was aided by various Western European nations, who, exhorted by the Pope and in a revival of crusading spirit, sent men, ships and supplies "to defend Christendom". Throughout the war, Venice maintained overall naval superiority, winning most naval engagements, but the efforts to blockade the Dardanelles were only partially successful, and the Republic never had enough ships to fully cut off the flow of supplies and reinforcements to Crete. The Ottomans were hampered in their efforts by domestic turmoil, as well as by the diversion of their forces north towards Transylvania and the Habsburg monarchy.

The prolonged conflict exhausted the economy of the Republic, which relied on the lucrative trade with the Ottoman Empire. By the 1660s, despite increased aid from other Christian nations, war-weariness had set in. The Ottomans on the other hand, having managed to sustain their forces on Crete and reinvigorated under the capable leadership of the Köprülü family, sent a final great expedition in 1666 under the direct supervision of the Grand Vizier. This began the final and bloodiest stage of the Siege of Candia, which lasted for more than two years. It ended with the negotiated surrender of the fortress, sealing the fate of the island and ending the war in an Ottoman victory. In the final peace treaty, Venice retained a few isolated island fortresses off Crete, and made some territorial gains in Dalmatia. The Venetian desire for a revanche would lead, barely 15 years later, to a renewed war, from which Venice would emerge victorious. Crete, however, would remain under Ottoman control until 1897, when it became an autonomous state; it was finally united with Greece in 1913.

The Morean War, also known as the Sixth Ottoman–Venetian War, was fought between 1684–1699 as part of the wider conflict known as the "Great Turkish War", between the Republic of Venice and the Ottoman Empire. Military operations ranged from Dalmatia to the Aegean Sea, but the war's major campaign was the Venetian conquest of the Morea (Peloponnese) peninsula in southern Greece. On the Venetian side, the war was fought to avenge the loss of Crete in the Cretan War (1645–1669). It happened while the Ottomans were entangled in their northern struggle against the Habsburgs – beginning with the failed Ottoman attempt to conquer Vienna and ending with the Habsburgs gaining Buda and the whole of Hungary, leaving the Ottoman Empire unable to concentrate its forces against the Venetians. As such, the Morean War was the only Ottoman–Venetian conflict from which Venice emerged victorious, gaining significant territory. Venice's expansionist revival would be short-lived, as its gains would be reversed by the Ottomans in 1718.

The Seventh Ottoman–Venetian War was fought between the Republic of Venice and the Ottoman Empire between 1714 and 1718. It was the last conflict between the two powers, and ended with an Ottoman victory and the loss of Venice's major possession in the Greek peninsula, the Peloponnese (Morea). Venice was saved from a greater defeat by the intervention of Austria in 1716. The Austrian victories led to the signing of the Treaty of Passarowitz in 1718, which ended the war. This war was also called the Second Morean War, the Small War or, in Croatia, the War of Sinj.

The fall of the Republic of Venice was a series of events that culminated on 12 May 1797 in the dissolution and dismemberment of the Republic of Venice at the hands of Napoleon Bonaparte and Habsburg Austria. In 1796, the young general Napoleon had been sent by the newly-formed French Republic to confront Austria, as part of the French Revolutionary Wars. He chose to go through Venice, which was officially neutral. Reluctantly, the Venetians allowed the formidable French army to enter their country so that it might confront Austria. However, the French covertly began supporting Jacobin revolutionaries within Venice, and the Venetian senate began quietly preparing for war. The Venetian armed forces were depleted and hardly a match for the battle-hardened French or even a local uprising. After the capture of Mantua on 2 February 1797, the French dropped any pretext and overtly called for revolution among the territories of Venice. By 13 March, there was open revolt, with Brescia and Bergamo breaking away. However, pro-Venetian sentiment remained high, and France was forced to reveal its true goals after it had provided military support to the underperforming revolutionaries. On 25 April, Napoleon openly threatened to declare war on Venice unless it democratised.