Roman mosaic from Rabat, Malta.

During the First Punic War of 218 BC, tensions lead the Maltese people to rebel against Carthage and turn control of their garrison over to the Roman Republic consul Sempronius. Malta remained loyal to Rome during the Syracusan revolt and the Romans rewarded it with the title Foederata Civitas, a designation that meant it would enjoy some autonomy although it fell within the jurisdiction of Sicilia province. The island, then known as Melita, had its capital located in the centre and this carried the same name; the city's present name is Mdina.

In 117 BC, the Maltese Islands were a thriving part of the Roman Empire, being promoted to the status of Municipium under Hadrian. During 60 AD, in the north of the island at Saint Paul's Bay, one of the apostles of Jesus Christ named Saint Paul was shipwrecked on the shores. Tradition holds he stayed in Malta for three months, introducing Christianity and performing various miracles. This is documented in the Bible in the Acts of the Apostles.

When the Roman Empire split into Eastern and Western divisions in the 4th century, Malta fell under the control of the Greek speaking Byzantine Empire which was ruled from Constantinople. Although Malta was under Byzantine rule for four centuries, not much is known from this period. There is evidence that Germanic tribes, including the Goths and Vandals, briefly took control of the islands before the Byzantines launched a counter attack and retook Malta.