The spiritual care of the Church of Antioch was vested in the Bishop of Antioch from the earliest years of Christianity. The first among the Bishops of Antioch was St. Peter who is believed to have established a church at Antioch in AD 33. Given the antiquity of the bishopric of Antioch and the importance of the Church in the city of Antioch which was a commercially significant city in the eastern parts of the Roman Empire, the Synod of Nicaea (AD 325) recognized the bishopric as a Patriarchate along with the bishoprics of Rome, Alexandria, and Jerusalem, bestowing authority for the Church in Antioch and All of the East on the Patriarch. (The Synod of Constantinople in AD 381 recognized the See of Constantinople also as a Patriarchate).

   Even though the Synod of Nicaea was convened by the Roman Emperor Constantine, the authority of the ecumenical synod was also accepted by the Church in the Persian Empire which was politically isolated from the Churches in the Roman Empire. Until AD 498, this Church accepted the spiritual authority of the Patriarch of Antioch. The Christological controversies that followed the Council of Chalcedon in AD 451resulted in a long struggle for the Patriarchate between those who accepted and those who rejected the Council. In AD 518, Patriarch Mor Severius was exiled from the city of Antioch and took refuge in Alexandria.

   On account of many historical upheavals and consequent hardships which the church had to undergo, the Patriarchate was transferred to different monasteries in Mesopotamia for centuries. In the 13th century it was transferred in the Monastery of Mor Hananyo (Deir al-Za`faran), near Mardin, Turkey, where it remained until 1933. Due to adverse political situation, it was transferred to Homs, Syria and in 1959 was transferred again to Damascus, Syria.