After the Second Punic War (202 BC), the Romans were casting about for a way to revenge themselves on Philip V of Macedonia for entering into an alliance with the Carthaginian general Hannibal. Pretexts were quickly found, but the underlying reason was Rome's designs for expansion in Greece.

War broke out in 200 BC; initially, the Aetolians and their allies remained neutral. But because their neutrality turned out to be advantageous to Philip V, they allied themselves with the Romans against him. Disappointed in a relationship which had promised a lot but proved to be of little profit to them, they entered into an alliance with the Greek king in Syria Antiochus III. That gave Rome the go-ahead to conquer Odysseus' celebrated land, motivated more by ambition than anything else. Thus, in 198 BC the Romans sent the consul M. Fulvius Nobili to Kefalonia to ask it's four cities to surrender and hand over 20 prominent citizens as hostages. When the hostages had been delivered and everything appeared calm, the city of Same closed its gates. Titus Livius writes that the Samians' reaction was spurred by a rumour that the Romans intended to evacuate the city and move in themselves. The siege lasted four months.

Finally, the exhausted Samians were forced to surrender in 189 BC. Between then and 30 BC, Kefalonia lost everything it had gained from its alliance with the Aetolians. Just as they had planned, the Romans turned the island into a base of operations from which their naval forces could patrol the area of Greece.
 

When Constantine reorganised the Roman Empire in 325 AD, Kefalonia became part of the Eparchy of Achaea. Attacks by barbarians (Vandals and Ostrogoths), as well as mandatory involvement in the Romans' wars with African emperors, often put the island in danger. The next time the empire was reorganised, under the emperor Heraclius in 629-634, it was divided into smaller themes (districts) which afforded it better protection from its enemies.