When Mehmed II was eleven years old he was sent to Amasya with his two lalas (advisors) to govern and thus gain experience, per the custom of Ottoman rulers before his time. Sultan Murad II also sent a number of teachers for him to study under. This Islamic education had a great impact in molding Mehmed's mindset and reinforcing his Muslim beliefs. He was influenced in his practice of Islamic epistemology by practitioners of science, particularly by his mentor, Molla Gürani, and he followed their approach. The influence of Akshamsaddin in Mehmed's life became predominant from a young age, especially in the imperative of fulfilling his Islamic duty to overthrow the Byzantine empire by conquering Constantinople.

In Mehmed II's first reign, he defeated the crusade led by John Hunyadi after the Hungarian incursions into his country broke the conditions of the truce Peace of Szeged in September 1444. Cardinal Julian Cesarini, the representative of the Pope, had convinced the king of Hungary that breaking the truce with Muslims was not a betrayal. At this time Mehmed II asked his father Murad II to reclaim the throne, but Murad II refused. According to the 17th-century chronicles, Mehmed II wrote, "If you are the sultan, come and lead your armies. If I am the sultan I hereby order you to come and lead my armies." Then, Murad II led the Ottoman army and won the Battle of Varna on 10 November 1444.

In 1448, John Hunyadi saw the right moment to lead a campaign against the Ottoman Empire. After the defeat at the Battle of Varna (1444), he raised another army to attack the Ottomans. His strategy was based on an expected revolt of the Balkan people, a surprise attack, and the destruction of the main force of the Ottomans in a single battle. In the three-day battle the Ottoman army under the command of Sultan Murad II defeated the Crusader army of regent John Hunyadi.

The first siege of Krujë occurred in 1450 when an Ottoman army of approximately 100,000 men laid siege to the Albanian town of Krujë. The League of Lezhë, led by Skanderbeg, experienced low morale after losing Svetigrad and Berat between 1448 and 1450. Nevertheless, Skanderbeg's exhortations and the support of the clergy, who claimed to have had visions of angels and victory, motivated the Albanians to defend the capital of the League, Krujë, at all costs. After leaving a protective garrison of 4,000 men under his trusted lieutenant Vrana Konti (also known as Kont Urani), Skanderbeg harassed the Ottoman camps around Krujë and attacked the supply caravans of Sultan Murad II's army. By September the Ottoman camp was in disarray as morale sank and disease ran rampant. The Ottoman army acknowledged that the castle of Krujë would not fall by strength of arms, lifted the siege, and made its way to Edirne. Soon thereafter, in the winter of 1450–51, Murad died in Edirne and was succeeded by his son, Mehmed II.

In 1446 Murad II returned to throne, Mehmed II retained the title of sultan but only acted as a governor of Manisa. Following death of Murad II in 1451, Mehmed II became sultan for second time. İbrahim Bey of Karaman invaded disputed area and instigated various revolts against Ottoman rule. Mehmed II conducted first campaign against İbrahim of Karaman; Byzantines threatened to release Ottoman claimant Orhan.

When Mehmed II ascended the throne again in 1451 he devoted himself to strengthening the Ottoman navy and made preparations for an attack on Constantinople. In the narrow Bosphorus Straits, the fortress Anadoluhisarı had been built by his great-grandfather Bayezid I on the Asian side; Mehmed erected an even stronger fortress called Rumelihisarı on the European side, and thus gained complete control of the strait. Having completed his fortresses, Mehmed proceeded to levy a toll on ships passing within reach of their cannon. A Venetian vessel ignoring signals to stop was sunk with a single shot and all the surviving sailors beheaded, except for the captain, who was impaled and mounted as a human scarecrow as a warning to further sailors on the strait.

The Ottoman fleet under Baltoghlu could not enter the Golden Horn due to the chain the Byzantines had previously stretched across the entrance. Mehmed ordered the construction of a road of greased logs across Galata on the north side of the Golden Horn, and dragged his ships over the hill, directly into the Golden Horn on 22 April, bypassing the chain barrier. This action seriously threatened the flow of supplies from Genoese ships from the nominally neutral colony of Pera, and it demoralized the Byzantine defenders.

Mehmed II's first campaigns after Constantinople were in the direction of Serbia. Mehmed led a campaign against Serbia because the Serbian ruler Đurađ Branković refused to send tribute and made an alliance with the Kingdom of Hungary. The Ottoman army conquered the important mining city of Novo Brdo. The Ottoman army advanced as far as Belgrade, where it attempted but failed to conquer the city from John Hunyadi at the Siege of Belgrade, on 14 July 1456.

After that the Serbian throne was offered to Stephen Tomašević, the future king of Bosnia, which infuriated Sultan Mehmed. Sultan Mehmed II decided to conquer Serbia completely and arrived at Smederevo; the new ruler did not even try to defend the city. After negotiations, Bosnians were allowed to leave the city and Serbia was officially conquered by Turks on June 20, 1459 ending the existence of the Serbian Despotate.

The Despotate of Morea refused to pay its annual tribute and revolted. In response Mehmed led a campaign into Morea. Mehmed entered the Morea in May 1460. The capital Mistra fell exactly seven years after Constantinople, on 29 May 1460. Demetrios ended up a prisoner of the Ottomans and his younger brother Thomas fled. By the end of the summer, the Ottomans had achieved the submission of virtually all cities possessed by the Greeks. The inhabitants were defeated and their territories were annexed into the Ottoman Empire.

After the emperor of the Empire of Trebizond refused to pay tribute and made an alliance with the Akkoyunlu Mehmed led a campaign against Trebizond by land and sea. He led a sizable army from Bursa by land and the Ottoman navy by sea, first to Sinope, joining forces with Ismail's brother Ahmed (the Red). He captured Sinope and ended the official reign of the Jandarid dynasty. After a siege of more than 32 days, Trebizond and the emperor surrendered and the Empire came to an end.

Vlad the Impaler who with Ottoman help had become the Ottoman vassal ruler of Wallachia, refused to pay tribute after some years and invaded Ottoman territory in northern Bulgaria. At that point Mehmed, with the main Ottoman army, was on the Trebizond campaign in Asia. When Mehmed returned from his Trebizond campaign he led a campaign against Wallachia. Vlad fled after some resistance to Hungary. Mehmed first made Wallachia an Ottoman eyalet but then appointed Vlad's brother Radu as a vassal ruler.

Mehmed invaded Bosnia and conquered it very quickly, executing Stephen Tomašević and his uncle Radivoj. Bosnia officially fell in 1463 and became the westernmost province of the Ottoman Empire.

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.

Although Mehmed occupied Karaman in 1468, he was unable to subjugate a number of Turkoman tribes living in the mountains which extended to the Mediterranean coast. These tribes were not subdued for the next fifty years, and from time to time rose in revolt around pretenders to the throne of Karamanids. After the death of the ruler of Karamanids a civil war began among his sons in which Uzun Hasan, ruler of the Akkoyunlu, also became involved. After some time Mehmed marched into the area and annexed the Karamanids to the Ottoman Empire.

Stephen III of Moldavia attacked Wallachia, an Ottoman vassal, and refused to pay the annual tribute. An Ottoman army was defeated and Mehmed led a personal campaign against Moldavia. He defeated the Moldavians in the Battle of Valea Alba, after that they accepted to pay the tribute and the peace was restored.

Mehmed led a campaign against Albania and besieged Krujë,but Albanian soldiers under Skanderbeg resisted successfully.

The attack on Otranto was part of an abortive attempt by the Ottomans to invade and conquer Italy. In the summer of 1480, a force of nearly 20,000 Ottoman Turks under the command of Gedik Ahmed Pasha invaded southern Italy. According to a traditional account, more than 800 inhabitants were beheaded after the city was captured.