After the fall of the Western Roman Empire, the city of Genoa was invaded by Germanic tribes, and, in about 643, Genoa and other Ligurian cities were captured by the Lombard Kingdom under the King Rothari. In 773 the Kingdom was annexed by the Frankish Empire; the first Carolingian count of Genoa was Ademarus, who was given the title praefectus civitatis Genuensis. During this time and in the following century Genoa was little more than a small centre, slowly building its merchant fleet, which was to become the leading commercial carrier of the Western Mediterranean. In 934–35 the town was thoroughly sacked and burned by a Fatimid fleet under Ya'qub ibn Ishaq al-Tamimi. This has led to discussion about whether early tenth-century Genoa was "hardly more than a fishing village" or a vibrant trading town worth attacking.

In the year 958, a diploma granted by Berengar II of Italy gave full legal freedom to the city of Genoa, guaranteeing the possession of its lands in the form of landed lordships.] At the end of the 11th century the municipality adopted a constitution, at a meeting consisting of the city's trade associations (compagnie) and of the lords of the surrounding valleys and coasts. The new city-state was termed a Compagna Communis. The local organization remained politically and socially significant for centuries. As late as 1382, the members of the Grand Council were classified by both the companion to which they belonged as well as by their political faction ("noble" versus "popular").

In 1015 and again in 1016 forces from the taifa of Denia, in the east of Muslim Spain (al-Andalus), attacked Sardinia and attempted to establish control over it. In both these years joint expeditions from the maritime republics of Pisa and Genoa repelled the invaders. These Pisan–Genoese expeditions to Sardinia were approved and supported by the Papacy, and modern historians often see them as proto-Crusades. After their victory, the Italian cities turned on each other, and the Pisans obtained hegemony over the island at the expense of their erstwhile ally. For this reason, the Christian sources for the expedition are primarily from Pisa, which celebrated its double victory over the Muslims and the Genoese with an inscription on the walls of its Duomo.

The Mahdia campaign of 1087 was a raid on the North African town of Mahdia by armed ships from the northern Italian maritime republics of Genoa and Pisa.

Mahdia had been the capital of Ifriqiya under the Fatimids, chosen due to its proximity to the sea which allowed them to conduct naval raids and expeditions such as the raid on Genoa in 935.

The raid had been prompted by the actions of the Zirid ruler Tamim ibn Muizz (reigned 1062–1108) as a pirate in waters off the Italian Peninsula, along with his involvement in Sicily fighting the Norman invasion. In this context, Tamin had ravaged the Calabrian coast in 1074, taking many slaves in the process, and capturing temporarily Mazara in Sicily in 1075 before negotiating a truce with Roger that ended Tamin's support for the emirs of Sicily.

These campaigns and raids by other Arab pirates threatened the growing economics interests of the Italian maritime republics and thus provided motivation for attacking the Zirid stronghold. This had led the Pisans to engage in military action before Mahdia, such as in briefly seizing of Bone in 1034 and military aiding the Norman conquest of Sicily in 1063.

Genoa started expanding during the First Crusade. At the time the city had a population of about 10,000. Twelve galleys, one ship and 1,200 soldiers from Genoa joined the crusade. The Genoese troops, led by noblemen de Insula and Avvocato, set sail in July 1097. The Genoese fleet transported and provided naval support to the crusaders, mainly during the siege of Antioch in 1098, when the Genoese fleet blockaded the city while the troops provided support during the siege. In the siege of Jerusalem in 1099 Genoese crossbowmen led by Guglielmo Embriaco acted as support units against the defenders of the city.

The Republic's role as a maritime power in the Mediterranean region secured many favorable commercial treaties for Genoese merchants. They came to control a large portion of the trade of the Byzantine Empire, Tripoli (Libya), the Principality of Antioch, Cilician Armenia, and Egypt. Although Genoa maintained free-trading rights in Egypt and Syria, it lost some of its territorial possessions after Saladin's campaigns in those areas in the late 12th century.

Over the course of the 11th and particularly the 12th centuries, Genoa became the dominant naval force in the Western Mediterranean, as its erstwhile rivals Pisa and Amalfi declined in importance. Genoa (along with Venice) succeeded in gaining a central position in the Mediterranean slave trade at this time.

After the capture of Antioch on May 3, 1098, Genoa forged an alliance with Bohemond of Taranto, who became the ruler of the Principality of Antioch. As a result, he granted them a headquarters, the church of San Giovanni, and 30 houses in Antioch. On May 6, 1098 a part of the Genoese army returned to Genoa with the relics of Saint John the Baptist, granted to the Republic of Genoa as part of their reward for providing military support to the First Crusade. Many settlements in the Middle East were given to Genoa as well as favorable commercial treaties.

Genoa later forged an alliance with King Baldwin I of Jerusalem (reigned 1100–1118). In order to secure the alliance Baldwin gave Genoa one-third of the Lordship of Arsuf, one-third of Caesarea, and one-third of Acre and its port's income. Additionally the Republic of Genoa would receive 300 bezants every year, and one-third of Baldwin's conquest every time 50 or more Genoese soldiers joined his troops.

The Republic's role as a maritime power in the region secured many favorable commercial treaties for Genoese merchants. They came to control a large portion of the trade of the Byzantine Empire, Tripoli (Libya), the Principality of Antioch, Cilician Armenia, and Egypt. Not all of Genoa's merchandise was so innocuous, however, as medieval Genoa became a major player in the slave trade. Although Genoa maintained free-trading rights in Egypt and Syria, it lost some of its territorial possessions after Saladin's campaigns in those areas in the late 12th century.

The commercial and cultural rivalry of Genoa and Venice was played out through the thirteenth century. The Republic of Venice played a significant role in the Fourth Crusade, diverting "Latin" energies to the ruin of its former patron and present trading rival, Constantinople. As a result, Venetian support of the newly established Latin Empire meant that Venetian trading rights were enforced, and Venice gained control of a large portion of the commerce of the eastern Mediterranean.

In order to regain control of the commerce, the Republic of Genoa allied with Michael VIII Palaiologos, emperor of Nicaea, who wanted to restore the Byzantine Empire by recapturing Constantinople. In March 1261 the treaty of the alliance was signed in Nymphaeum. On July 25, 1261, Nicaean troops under Alexios Strategopoulos recaptured Constantinople.

As a result, the balance of favour tipped toward Genoa, which was granted free trade rights in the Nicene Empire. Besides the control of commerce in the hands of Genoese merchants, Genoa received ports and way stations in many islands and settlements in the Aegean Sea. The islands of Chios and Lesbos became commercial stations of Genoa as well as the city of Smyrna (Izmir).

The Genoese–Mongol Wars were a series of conflicts fought between the Republic of Genoa, the Mongol Empire and its successor states, most notedly the Golden Horde and Crimean Khanate. The wars were fought over control of trade and political influence in the Black Sea and Crimean peninsula during the 13th, 14th and 15th centuries.

Interactions between the Republic of Genoa and the Mongol Empire began in the early 13th century, as the Mongol invasion of Europe pushed further west. The successful invasions of Kievan Rus', Cumania and Bulgaria in the 1240s established Mongol control of the Crimean peninsula, allowing for the empire to exert influence in the Black Sea.

The Italian city state of Genoa, already the controller of a trading empire in the Mediterranean, was eager to expand its trading power in the region. Genoese merchants had been active in the Black Sea since the mid 13th century, spurred on by the signing of the Treaty of Nymphaeum in 1261 and the Byzantine recapture of Constantinople. Taking advantage of its treaty with the Byzantine Empire and its client states, Genoa established a number of trading colonies (Gazaria) in the Black Sea, Crimean peninsula, Anatolia, and Romania. Most notable among these colonies was Kaffa, which anchored Genoese trade with the near east.

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.

Genoa and Pisa became the only states with trading rights in the Black Sea. In the same century the Republic conquered many settlements in Crimea, where the Genoese colony of Caffa was established. The alliance with the restored Byzantine Empire increased the wealth and power of Genoa, and simultaneously decreased Venetian and Pisan commerce. The Byzantine Empire had granted the majority of free trading rights to Genoa. In 1282 Pisa tried to gain control of the commerce and administration of Corsica, after being called for support by the judge Sinucello who revolted against Genoa.

In August 1282, part of the Genoese fleet blockaded Pisan commerce near the river Arno. During 1283 both Genoa and Pisa made war preparations. Genoa built 120 galleys, 60 of which belonged to the Republic, while the other 60 galleys were rented to individuals. More than 15,000 mercenaries were hired as rowmen and soldiers. The Pisan fleet avoided combat, and tried to wear out the Genoese fleet during 1283. On August 5, 1284, in the naval Battle of Meloria the Genoese fleet, consisting of 93 ships led by Oberto Doria and Benedetto I Zaccaria, defeated the Pisan fleet, which consisted of 72 ships and was led by Albertino Morosini and Ugolino della Gherardesca. Genoa captured 30 Pisan ships, and sank seven. About 8,000 Pisans were killed during the battle, more than half of the Pisan troops, which were about 14,000. The defeat of Pisa, which never fully recovered as a maritime competitor, resulted in gain of control of the commerce of Corsica by Genoa. The Sardinian town of Sassari, which was under Pisan control, became a commune or self-styled "free municipality" which was controlled by Genoa. Control of Sardinia, however, did not pass permanently to Genoa: the Aragonese kings of Naples disputed control and did not secure it until the fifteenth century.

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.

Carried by twelve Genoese galleys, plague arrived by ship in Sicily in October 1347; the disease spread rapidly all over the island. Galleys from Kaffa reached Genoa and Venice in January 1348, but it was the outbreak in Pisa a few weeks later that was the entry point to northern Italy. Towards the end of January, one of the galleys expelled from Italy arrived in Marseilles.

From Italy, the disease spread northwest across Europe, striking France, Spain (the epidemic began to wreak havoc first on the Crown of Aragon in the spring of 1348), Portugal and England by June 1348, then spread east and north through Germany, Scotland and Scandinavia from 1348 to 1350. It was introduced into Norway in 1349 when a ship landed at Askøy, then spread to Bjørgvin (modern Bergen) and Iceland. Finally, it spread to northwestern Russia in 1351. Plague was somewhat more uncommon in parts of Europe with less developed trade with their neighbours, including the majority of the Basque Country, isolated parts of Belgium and the Netherlands, and isolated Alpine villages throughout the continent.

The Genoese held the colony of Galata, a suburb of Constantinople across the Golden Horn, as part of the Treaty of Nymphaeum of 1261. This agreement established trade relations between the two powers and granted Genoa extensive privileges within the empire, including the right to collect customs dues at Galata. The Byzantine Empire was still reeling from the civil war of 1341–1347, and these concessions made a recovery difficult. Constantinople collected only thirteen percent of all custom dues from shipping passing through the Bosphorus, only 30,000 hyperpyra a year, with the rest going to Genoa.

The Byzantine–Genoese War of 1348–1349 was fought over control over custom dues through the Bosphorus. The Byzantines attempted to break their dependence for food and maritime commerce on the Genoese merchants of Galata, and also to rebuild their own naval power. Their newly constructed navy however was captured by the Genoese, and a peace agreement was concluded.

The failure of the Byzantines to expel the Genoese from Galata meant that they could never restore their sea power, and would thenceforth be dependent either on Genoa or Venice for naval aid. From 1350, the Byzantines allied themselves to the Republic of Venice, which was also at war with Genoa. However, as Galata remained defiant, the Byzantines were forced to settle the conflict in a compromise peace in May 1352.

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.

The two maritime powers, Genoa and Venice, had long been leading commercial powers with ties to Constantinople that had nurtured their growth during the Early Middle Ages. Their rivalry over trade with the Levant had generated a number of wars. Genoa, having suffered previous defeats at the hands of the Venetians, had emerged from submission to the Visconti tyrants of Milan during the 14th century, although it had also been severely weakened by the Black Death of 1348 which took a toll of 40,000 on the city. Venice had participated in the dismemberment of the Byzantine Empire in 1204 and gradually taken over land on the Adriatic, entering into conflict with Hungary; on the Italian mainland, its terrestrial acquisition had generated a rivalry with the nearby largest city, Padua.

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 of Chioggia 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.

In 1396, in order to protect the republic from internal unrest and the provocations of the Duke of Orléans and the former Duke of Milan, the Doge of Genoa Antoniotto Adorno made Charles VI of France the difensor del comune ("defender of the municipality") of Genoa. Though the republic had previously been under partial foreign control, this marked the first time Genoa was dominated by a foreign power.

In the 15th century two of the earliest banks in the world were founded in Genoa: the Bank of Saint George, founded in 1407, which was the oldest state deposit bank in the world at its closure in 1805 and the Banca Carige, founded in 1483 as a mount of piety, which still exists.

Threatened by Alfonso V of Aragon, the Doge of Genoa in 1458 handed the Republic over to the French, making it the Duchy of Genoa under the control of John of Anjou, a French royal governor. However, with support from Milan, Genoa revolted and the Republic was restored in 1461. The Milanese then changed sides, conquering Genoa in 1464 and holding it as a fief of the French crown. Between 1463–1478 and 1488–1499, Genoa was held by the Milanese House of Sforza. From 1499 to 1528, the Republic reached its nadir, being under nearly continual French occupation. The Spanish, with their intramural allies, the "old nobility" entrenched in the mountain fastnesses behind Genoa, captured the city on May 30, 1522, and subjected the city to a pillage. When the admiral Andrea Doria of the powerful Doria family allied with the Emperor Charles V to oust the French and restore Genoa's independence, a renewed prospect opened: 1528 marks the first loan from Genoese banks to Charles.

Under the ensuing economic recovery, many aristocratic Genoese families, such as the Balbi, Doria, Grimaldi, Pallavicini, and Serra, amassed tremendous fortunes. According to Felipe Fernandez-Armesto and others, the practices Genoa developed in the Mediterranean (such as chattel slavery) were crucial in the exploration and exploitation of the New World.

At the time of Genoa's peak in the 16th century, the city attracted many artists, including Rubens, Caravaggio and Van Dyck. The architect Galeazzo Alessi (1512–1572) designed many of the city's splendid palazzi, as did in the decades that followed by fifty years Bartolomeo Bianco (1590–1657), designer of centrepieces of University of Genoa. A number of Genoese Baroque and Rococo artists settled elsewhere and a number of local artists became prominent.

From about 1520 the Genoese controlled the port of Panama, the first port on the Pacific founded by the conquest of the Americas; the Genoese obtained a concession to exploit the port mainly for the slave trade of the new world on the Pacific, until the destruction of the primeval city in 1671.

Thereafter, Genoa underwent something of a revival as a junior associate of the Spanish Empire, with Genoese bankers, in particular, financing many of the Spanish crown's foreign endeavors from their counting houses in Seville. Fernand Braudel has even called the period 1557 to 1627 the "age of the Genoese", "of a rule that was so discreet and sophisticated that historians for a long time failed to notice it", although the modern visitor passing brilliant Mannerist and Baroque palazzo facades along Genoa's Strada Nova (now Via Garibaldi) or via Balbi cannot fail to notice that there was conspicuous wealth, which in fact was not Genoese but concentrated in the hands of a tightly knit circle of banker-financiers, true "venture capitalists". Genoa's trade, however, remained closely dependent on control of Mediterranean sealanes, and the loss of Chios to the Ottoman Empire (1566), struck a severe blow.

The opening for the Genoese banking consortium was the state bankruptcy of Philip II in 1557, which threw the German banking houses into chaos and ended the reign of the Fuggers as Spanish financiers. The Genoese bankers provided the unwieldy Habsburg system with fluid credit and a dependably regular income. In return the less dependable shipments of American silver were rapidly transferred from Seville to Genoa, to provide capital for further ventures.

The Relief of Genoa took place between 28 March 1625 and 24 April 1625, during the Thirty Years' War. It was a major naval expedition launched by Spain against the French-occupied Republic of Genoa, of which the capital Genoa was being besieged by a joint Franco-Savoyard army composed of 30,000 men and 3,000 cavalry.

In 1625, when the Republic of Genoa, traditionally an ally of Spain, was occupied by French troops of the Duke of Savoy, the city underwent a hard siege. It was known in Genoese governmental circles that one of the reasons why the Dutch government had offered their help to the Franco-Savoyan army was so that they could "hit the bank of the King of Spain".

However, the Spanish fleet commanded by General Álvaro de Bazán, Marquis of Santa Cruz, came to the aid of Genoa and relieved the city. Returning its sovereignty to the Republic of Genoa and forcing the French to raise the siege, they consequently began a combined campaign against the Franco-Savoyan forces that had overrun the Genoese Republic one year before. The joint Franco-Piedmontese army was forced to leave Liguria and Spanish troops invaded Piedmont, thereby securing the Spanish Road. Richelieu's Invasion of Genoa and the Valtelline had resulted in his humiliation by the Spaniards.

The Genoese banker Ambrogio Spinola, Marquess of Los Balbases, for instance, raised and led an army that fought in the Eighty Years' War in the Netherlands in the early 17th century. The decline of Spain in the 17th century brought also the renewed decline of Genoa, and the Spanish crown's frequent bankruptcies, in particular, ruined many of Genoa's merchant houses. In 1684 the city was heavily bombarded by a French fleet as punishment for its alliance with Spain.

The Naples Plague refers to a plague epidemic in Italy between 1656–1658 that nearly eradicated the population of Naples. In Genoa, approximately 60,000 lives were lost due to the epidemic, accounting for 60% of the local population.

On 26 June 1745, the Republic of Genoa declared war on the Kingdom of Sardinia. This decision would prove disastrous for Genoa, which later surrendered to the Austrians in September 1746 and was briefly occupied before a revolt liberated the city two months later. The Austrians returned in 1747 and, along with a contingent of Sardinian forces, laid siege to Genoa before being driven off by the approach of a Franco-Spanish army.

Though Genoa retained its lands in the Peace of Aix-la-Chapelle, it was unable to keep its hold on Corsica in its weakened state. After driving out the Genoese, the Corsican Republic was declared in 1755. Eventually relying on French intervention to quash the rebellion, Genoa was forced to cede Corsica to the French in the 1768 Treaty of Versailles.

Already in 1794 and 1795 the revolutionary echoes from France reached Genoa, thanks to Genoese propagandists and refugees sheltered in the nearby state of the Alps, and in 1794 a conspiracy against the aristocratic and oligarchic ruling class that, in fact, was already waiting for it in the Genoese palaces of power. However, it was in May 1797 that the intent of the Genoese jacobins and French citizens to overthrow the government of the Doge Giacomo Maria Brignole took shape, giving rise to a fratricidal war in the streets between opponents and popular supporters of the current customs system.

The direct intervention of Napoleon (during the Campaigns of 1796) and his representatives in Genoa was the final act that led to the fall of the Republic in early June, who overthrew the old elites which had ruled the state for all of its history, giving birth to the Ligurian Republic on June 14, 1797, under the watchful care of Napoleonic France. After Bonaparte's seizure of power in France, a more conservative constitution was enacted, but the Ligurian Republic's life was short—in 1805 it was annexed by France, becoming the départements of Apennins, Gênes, and Montenotte.