In 330, Constantine moved the seat of the Empire to Constantinople, which he founded as a second Rome on the site of Byzantium, a city strategically located on the trade routes between Europe and Asia and between the Mediterranean and the Black Sea. Constantine introduced important changes into the Empire's military, monetary, civil and religious institutions. As regards his economic policies in particular, he has been accused by certain scholars of "reckless fiscality", but the gold solidus he introduced became a stable currency that transformed the economy and promoted development.

Under Constantine, Christianity did not become the exclusive religion of the state, but enjoyed imperial preference, because the emperor supported it with generous privileges. Constantine established the principle that emperors could not settle questions of doctrine on their own, but should summon instead general ecclesiastical councils for that purpose. His convening of both the Synod of Arles and the First Council of Nicaea indicated his interest in the unity of the Church, and showcased his claim to be its head.

The Roman Empire during the reigns of Leo I (east) and Majorian (west) in 460 AD. Roman rule in the west would last less than two more decades, whereas the territory of the east would remain static until the reconquests of Justinian I.

In 395, Theodosius I bequeathed the imperial office jointly to his sons: Arcadius in the East and Honorius in the West, once again dividing Imperial administration. In the 5th century the Eastern part of the empire was largely spared the difficulties faced by the West—due in part to a more established urban culture and greater financial resources, which allowed it to placate invaders with tribute and pay foreign mercenaries. This success allowed Theodosius II to focus on the codification of the Roman law and the further fortification of the walls of Constantinople, which left the city impervious to most attacks until 1204.

To fend off the Huns, Theodosius had to pay an enormous annual tribute to Attila. His successor, Marcian, refused to continue to pay the tribute, but Attila had already diverted his attention to the West. After his death in 453, the Hunnic Empire collapsed, and many of the remaining Huns were often hired as mercenaries by Constantinople.