The name comes from the church around which in about the year one thousand, the population was grouped by the Cassinesi abbots to protect them against the Saracen invasions.
In Cassino Abbey archives it was mentioned for the first time in the documents of 961 when the abbey received a large territory of Cassino in donations from the Lombard princes. The town has always been in close contact with the Benedictines to whom they had to pay a tenth of the produce of the land and a third of the wine, but they could graze their cattle.
At the beginning of the sixteenth century it was involved in the wars between Spain and France and was plundered by the papal troops.
After Italian unification Sant’Ambrogio saw a massive emigration until the 1920s when a bridge was built over the Garigliano.
During World War II the Germans put their operational commands in Sant’Ambrogio sul Garigliano and subsequently, the town was almost completely destroyed.