Of Volscan origin, after the fall of the Western Roman Empire Isola del Liri was ruled by the Byzantines and then the Lombards.

In the early Middle Ages the town was, alternatively, under the rule of the Byzantines and the Lombards, until it became part of the county of Sora in the Principality of Capua.

It was also housed by their successors as dukes, the Boncompagni; in the 17th century Costanza Sforza turned into a luxurious palace, with biblica frescoes and basreliefs of the duchy's lands, as well as a garden.

About 2 kilometres (1.2 mi) north of the town is the church of San Domenico, erected in the 12th century, which is said to mark the site of the villa of Cicero.

In 1997, for the 10th edition of the festival, the town of Isola del Liri signed a twinning with the city of New Orleans (Louisiana, USA).