The initial Ottoman–Safavid conflict culminated in the Battle of Chaldiran in 1514, and was followed by a century of border confrontation. The Battle of Chaldiran ended with a decisive victory for the Ottoman Empire over the Safavid Empire. As a result, the Ottomans annexed Eastern Anatolia and northern Iraq from Safavid Iran. It marked the first Ottoman expansion into Eastern Anatolia (Western Armenia), and the halt of the Safavid expansion to the west.^[20] The Chaldiran battle was just the beginning of 41 years of destructive war, which only ended in 1555 with the Treaty of Amasya. Though Mesopotamia and Eastern Anatolia (Western Armenia) were eventually reconquered by the Safavids under the reign of Shah Abbas the Great (r. 1588–1629), they would be permanently ceded to the Ottomans by the 1639 Treaty of Zuhab.

At Chaldiran, the Ottomans had a larger, better equipped army numbering 60,000 to 100,000 as well as many heavy artillery pieces, while the Safavid army numbered some 40,000 to 80,000 and did not have artillery at its disposal. Ismail I, the leader of the Safavids, was wounded and almost captured during the battle. His wives were captured by the Ottoman leader Selim I, with at least one married off to one of Selim's statesmen. Ismail retired to his palace and withdrew from government administration after this defeat and never again participated in a military campaign. After their victory, Ottoman forces marched deeper into Persia, briefly occupying the Safavid capital, Tabriz, and thoroughly looting the Persian imperial treasury. The battle is one of major historical importance because it not only negated the idea that the Murshid of the Shia-Qizilbash was infallible, but also led Kurdish chiefs to assert their authority and switch their allegiance from the Safavids to the Ottomans.