The diocese included originally all Middle Eastern provinces of the Empire: Isauria, Cilicia, Cyprus, Euphratensis, Mesopotamia, Osroene, Syria Coele, Phoenice, Palaestina Prima, Palaestina Secunda, Arabia, and the Egyptian provinces Aegyptus, Augustamnica, Thebais, Libya Superior and Libya Inferior, which were grouped into the separate Diocese of Egypt under Valens (r.

The last creation of a new province dated in the reign of Justinian I (r. 527–565), when Theodorias, the region around Laodicea, was split off from Syria I.

[2] In 535, as part of his administrative reforms, Justinian I abolished the diocese, and the comes Orientis became the provincial governor of Syria I, while retaining his previous rank of vir spectabilis and his salary.

Shortly after the Byzantine victory in the war and the recovery of the region, it was again lost, this time permanently except Cilicia and most of the Levantine coasts later reconquered, to the Muslim conquests: by the 640s, Cilicia formed the border (Al-Awasim) between Byzantium and the new Arab Rashidun Caliphate and its successors, while Cyprus became a disputed territory.

From the old provinces of the Diocese of the East, only Isauria and parts of the two Cilicias remained under Byzantine rule, grouped under the new Anatolic Theme.