According to a legend, the mythical hero Hercules founded the city[3] after his victory over the Lestrigones, a population of giant cannibals living in southern Lazio.

The historical Setia appeared around the 5th century BC as the Volscan settlement member of the Latin League.

It became a Roman colony in 382 BC[3] and flourished because of its strategic and commercial position near the "pedemontana" way and the Appian Way, the road that connected Rome to southern Italy.

In the early Middle Ages, Sezze experienced trouble due to its location near the main road of communication.

The semi-autonomous status lasted until, after decades of skirmishes and wars with neighboring Sermoneta and Priverno, Sezze was conquered by the troops of the Caetani family in 1381.

The Setini rebelled, exterminating the garrison: they avoided a bitter revenge only by paying a large sum of money.

During World War II, American bombardment destroyed some churches and buildings in the historical center.