The city played a noted role in the final battles of the First Punic War. In 242 BC a fleet of 200 quinqueremes under the consul Gaius Lutatius Catulus and assisted by the praetor Quintus Valerius Falto arrived to blockade the harbor of Lilybaeum and place the city under siege. The intent appeared to be to cut Hamilcar Barca's supply and communications lines, so the Carthaginians sent a fleet of 250 warships under Hanno to break the blockade. Hanno halted his fleet off the Aegates Islands to wait for a favourable breeze that would speed him to Lilybaeum, but the Carthaginian fleet was spotted by Roman scouts and Catulus abandoned the blockade to engage the enemy. On March 10 the wind was favorable for Carthage and Hanno moved toward Lilybaeum, only to find the Roman commander Catulus risking battle despite unfavorable conditions. The resulting battle of the Aegates Islands was a decisive Roman victory, allowing Catulus to resume the siege and conquer Lilybaeum. Carthage subsequently admitted defeat and signed a peace treaty with Rome, bringing the First Punic War to a conclusion.

In the later wars it was a starting point for the Roman expeditions against Carthage, and under Roman rule it enjoyed considerable prosperity. Marcus Tullius Cicero, when elected Quaestor in 76 BC, was assigned to Lilybaeum; his work there led to his later prosecution of the Sicilian Praetor Verres. Lilybaeum obtained municipal rights from Augustus and became a colony under either Helvius Pertinax or Septimius Severus. At the beginning of the fifth century, the town was sacked by the Vandals. The presence of a Christian community in the Roman town is documented since the time of Pope Zosimus, when the diocese of Lilybaeum was founded.

The Saracens, who ruled Sicily during the tenth century AD, gave it its present name, Marsa Allah—port of Allah. The harbor that lay on the northeast was destroyed by Charles V to prevent its occupation by pirates. The modern harbor lies to the southeast.