Suleiman the Magnificent first put down a revolt led by the Ottoman-appointed governor in Damascus. By August, 1521, Suleiman had captured the city of Belgrade, which was then under Hungarian control. In 1522, Suleiman captured Rhodes. On August 29, 1526, Suleiman defeated Louis II of Hungary at the Battle of Mohács. In 1541 Suleiman annexed most of present-day Hungary, known as the Great Alföld, and installed Zápolya's family as rulers of the independent principality of Transylvania, a vassal state of the Empire. While claiming the entire kingdom, Ferdinand I of Austria ruled over the so-called "Royal Hungary" (present-day Slovakia, North-Western Hungary and western Croatia), a territory which temporarily fixed the border between the Habsburgs and the Ottomans.

The Shi'ite Safavid Empire ruled Persia and modern-day Iraq. Suleiman waged three campaigns against the Safavids. In the first, the historically important city of Baghdad fell to Suleiman's forces in 1534. The second campaign, 1548–1549, resulted in temporary Ottoman gains in Tabriz and Azerbaijan, a lasting presence in Van Province, and some forts in Georgia. The third campaign (1554–55) was a response to costly Safavid raids into the provinces of Van and Erzurum in eastern Anatolia in 1550–52. Ottoman forces captured Yerevan, Karabakh and Nakhjuwan and destroyed palaces, villas and gardens. Although Sulieman threatened Ardabil, the military situation was essentially a stalemate by the end of the 1554 campaign season. Tahmasp sent an ambassador to Suleiman's winter quarters in Erzurum in September 1554 to sue for peace. Influenced at least in part by the Ottoman Empire's military position with respect to Hungary, Sulieman agreed to temporary terms. The formal Peace of Amasya signed the following June was the first formal diplomatic recognition of the Safavid Empire by the Ottomans. Under the Peace, the Ottomans agreed to restore Yerevan, Karabakh and Nakhjuwan to the Safavids and in turn would retain Iraq and eastern Anatolia. Suleiman agreed to permit Safavid Shi’a pilgrims to make pilgrimages to Mecca and Medina as well as tombs of imams in Iraq and Arabia on condition that the shah abolished the taburru, the cursing of the first three Rashidun caliphs. The Peace ended hostilities between the two empires for 20 years.

Huge territories of North Africa up to west of Algeria were annexed. The Barbary States of Tripolitania, Tunisia and Algeria became provinces of the Empire. The piracy carried on thereafter by the Barbary pirates of North Africa remained part of the wars against Spain, and the Ottoman expansion was associated with naval dominance for a short period in the Mediterranean. Ottoman navies also controlled the Red Sea, and held the Persian Gulf until 1554, when their ships were defeated by the navy of the Portuguese Empire in the Battle of the Gulf of Oman. The Portuguese would continue to contest Suleiman's forces for control of Aden. In 1533 Khair ad Din known to Europeans as Barbarossa, was made Admiral-in-Chief of the Ottoman navies who were actively fighting the Spanish navy.

In 1535 the Habsburg Holy Roman Emperor, Charles V (Charles I of Spain) won an important victory against the Ottomans at Tunis, but in 1536 King Francis I of France allied himself with Suleiman against Charles. In 1538, the fleet of Charles V was defeated at the Battle of Preveza by Khair ad Din, securing the eastern Mediterranean for the Turks for 33 years. Francis I asked for help from Suleiman, then sent a fleet headed by Khair ad Din who was victorious over the Spaniards, and managed to retake Naples from them. Suleiman bestowed on him the title of beylerbey. One result of the alliance was the fierce sea duel between Dragut and Andrea Doria, which left the northern Mediterranean and the southern Mediterranean in Ottoman's hands.