In 215 BCE, Hiero's grandson, Hieronymus, came to the throne on his grandfather's death and Syracuse fell under the influence of an anti-Roman faction, including two of his uncles, amongst the Syracusan elite.

Despite diplomatic attempts, war broke out between the Roman Republic and the Kingdom of Syracuse in 214 BCE, while the Romans were still busy battling with Carthage at the height of the Second Punic War (218–201 BCE).

A Roman force led by the proconsul Marcus Claudius Marcellus consequently laid siege to the port city by sea and land in 213 BCE. The city of Syracuse, located on the eastern coast of Sicily was renowned for its significant fortifications, great walls that protected the city from attack. Among the Syracuse defenders was the mathematician and scientist Archimedes.

A large Carthaginian army led by Himilco was sent to relieve the city in 213 BCE and several further Sicilian cities deserted the Romans. In the spring of 212 BCE the Romans stormed Syracuse in a surprise night assault and captured several districts of the city. Meanwhile, the Carthaginian army was crippled by plague. After the Carthaginians failed to resupply the city, the rest of Syracuse fell in the autumn of 212 BCE; Archimedes was killed by a Roman soldier.