637, during the reign of the Byzantine emperor Heraclius, Antioch was conquered by the Rashidun Caliphate during the Battle of the Iron Bridge. The city became known in Arabic as أنطاكيّة (Antākiyyah). Since the Umayyad dynasty was unable to penetrate the Anatolian plateau, Antioch found itself on the frontline of the conflicts between two hostile empires during the next 350 years, so that the city went into a precipitous decline.

In 969, the city was recovered for the Byzantine Emperor Nikephoros II Phokas by Michael Bourtzes and the stratopedarches Peter. It soon became the seat of a doux, the civil governor of the homonymous theme, but also the seat of the somewhat more important Domestic of the Schools of the Orient, the supreme military commander of the imperial forces on the eastern frontier. Sometimes both offices were held by the same person, usually military officers such as Nikephoros Ouranos, or Philaretos Brachamios, who managed to retain the integrity of the eastern borderline after the Seljuk conquest of Anatolia. As the empire disintegrated rapidly before the Komnenian restoration, Dux of Antioch & Domestic of the Schools of the East Philaretos Brachamios held the city until the Seljuk Turks captured it from him in 1084. The Sultanate of Rum held it only fourteen years before the Crusaders arrived.