The first major conflict between Arab invaders and Persian forces in Mesopotamia occurred in 634 CE at the Battle of the Bridge. Here, a Muslim force of about 5,000, led by Abū ʿUbayd ath-Thaqafī, suffered defeat at the hands of the Persians. This setback was followed by Khalid ibn al-Walid's successful campaign, which resulted in the Arab conquest of almost all of Iraq within a year, except for Ctesiphon, the Persian capital.

A pivotal moment came around 636 CE, when a larger Arab Muslim force under Saʿd ibn Abī Waqqās defeated the main Persian army at the Battle of al-Qādisiyyah. This victory paved the way for the capture of Ctesiphon. By the end of 638 CE, the Muslims had conquered all Western Sassanid provinces, including modern-day Iraq. The last Sassanid Emperor, Yazdegerd III, fled first to central and then northern Persia, where he was killed in 651 CE.

The Islamic conquests marked the most extensive Semitic expansions in history. The Arab conquerors established new garrison cities, notably al-Kūfah near ancient Babylon and Basrah in the south. However, the north of Iraq remained predominantly Assyrian and Arab Christian in character.