Legend has it that Sezze was founded by Hercules and its name comes from the lion hair with which the hero used to cover himself. The lion is depicted on the emblem of the city.

Conquered by Rome, it was then chosen to guard the Carthaginian prisoners during the Second Punic War due to its isolated position and being fortified. In the Roman period Sezze was famous for the quality of its wines, praised by Marzial, Juvenal, and Cicero.

In the Middle Ages it has had many ups and downs since it was along the way of the foothills of communication between the north and the south of Lazio, and was chosen as a place to stay by the popes: Gregory VII, Paschal II and Lucio III.

In 1690 in Sezze the Literary Scientific Academy of the Argonauts was founded, one of the first in Italy.