The island flourished during the reign of the descendants of Alexander the Great, more specifically of Antigon the First, who founded "Kinon ton Nisioton", a confederation of the Cyclades.

The island experienced a period of great economic activity and development of trade with Delos.

Under Roman rule, the island prospered, increasing the commercial value of the port of Syros.

Numerous coins of that period were found, as well as engraved inscriptions at ormo Grammata.

The islanders worshipped Posseidon, Zeus, Athina, Dimitra, Pan, Hermes, Dionysios, and other gods.

According to manuscripts of Bishop Irinei of 307 A.D., Christianity came to Syros in the 4th century A.D. It was part of the Byzantine Council of Aegeos, first belonging to the episcopate of Delos, then to that of Athens, and finally to that of Keas-Sermion-Sifnos.

In the 4th century A.D., earthquakes and constant pirate invasions destroyed the better part of the island.

In 747-750 A.D., the plague decimated its population. Pirates continued their incursions into the island, forcing the survivors of the plague to withdraw to a hill above the port, where they settled and which developed into the town which today is called Ano Syros.

At that time, Syros bore the name of Souda.