In the third century BC Epirus remained a substantial power, and the Epirotes attempted to gain control of Macedonia, but in the 2nd century they blundered into war against the Romans, and in 168 BC the Romans pillaged the country and effectively ended its independence. In 146 BC it became part of the province of Roman Macedonia, receiving the name Epirus Vetus, to distinguish it from Epirus Nova to the east.

For the next 400 years Epirus was ruled from Rome, until in the 4th century AD it passed to the rule of Constantinople. It was overrun and largely resettled by successive waves of Goths, Slavs, Vlachs and Albanians, and its Greek character was diluted without ever being entirely lost. When Constantinople fell to the Fourth Crusade in 1204, Michel Angelus Comnenus seized Aetolia and Epirus, and his family ruled the area until 1318.