Following the reforms of Diocletian, Syria Coele became part of the Diocese of Oriens.

Sometime between 330 and 350 (likely c. 341), the province of Euphratensis was created out of the territory of Syria Coele along the western bank of the Euphrates and the former realm of Commagene, with Hierapolis as its capital.

After c. 415 Syria Coele is further subdivided into Syria I (or Syria Prima), with the capital remaining at Antioch, and Syria II (Syria Secunda) or Syria Salutaris, with capital at Apamea on the Orontes.

In 528, Justinian I carves out the small coastal province, Theodorias, out of territory from both provinces.

The region remains one of the most important provinces of the Byzantine Empire.

It is occupied by the Sassanids between 609 and 628, then recovered by the emperor Heraclius, but irreversibly lost again to the advancing Muslims after the battle of Yarmouk and the fall of Antioch.