Mehmed II was born in Edirne, then the capital city of the Ottoman state. His father was Sultan Murad II (1404–1451) and his mother Hüma Hatun, a slave of uncertain origin.

After Murad II made peace with Hungary on June 12, 1444, he abdicated the throne to his 12-year-old son Mehmed II in July/August 1444.

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.

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.

The attacking Ottoman army, which significantly outnumbered Constantinople's defenders, was commanded by the 21-year-old Sultan Mehmed II (later called "the Conqueror"), while the Byzantine army was led by Emperor Constantine XI Palaiologos. After conquering the city, Mehmed II made Constantinople the new Ottoman capital, replacing Adrianople. The Fall of Constantinople marked the end of the Byzantine Empire, and effectively the end of the Roman Empire, a state which dated back to 27 BC and lasted nearly 1,500 years. The capture of Constantinople, a city which marked the divide between Europe and Asia Minor, also allowed the Ottomans to more effectively invade mainland Europe, eventually leading to Ottoman control of much of the Balkan peninsula.

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.

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.

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.