The Edict of Milan (313 AD), which put an end to persecution and encouraged the spread of Christianity, and the decision by Constantine the Great to move the capital of the Empire from Rome to Byzantium, the ancient Greek colony on the Bosphorus (324 AD), renamed Constantinople in his honour, mark the beginning of a period with distinct characteristics and a civilisation that came to be called Byzantine. Crete’s privileged position at the centre of the eastern Mediterranean made it an important trading post to and from the new capital.

Herakleion’s status was probably enhanced when Crete became part of the province of Eastern Illyricum and came under the administrative jurisdiction of Constantinople. The transfer of the capital to the east and the loss of the eastern provinces of the empire in the time of Justinian probably determined the fate of the city, which gradually developed into a major trading centre between Crete, the Aegean islands and the new capital.

The massive earthquake and tsunami that struck Crete in 365 AD caused severe damage to most of the ancient cities, including Heraklion. Reconstruction was interrupted by further disasters in the 5th century. These events, combined with the administrative reorganisation of the empire from the 4th century onwards and the new religious needs arising from the gradual spread and organisation of Christian worship, led to reconstruction and significant urban changes.

The fact that Herakleion does not appear among the Cretan cities mentioned in the Synacdemus of Hierocles (before 535 AD) may indicate that in the 5th century it was still under the administrative jurisdiction of Knossos, since the term polis in this period seems to have referred only to settlements of the highest administrative level. However, this situation had changed by the end of the 7th century, as Civitas Eraclium is recorded among the 24 cities of Crete in the so-called Chronography of the Anonymous of Ravenna.