It is one of several Italian comuni named "Cantalupo" ("song of the wolf" or "howl of the wolf" or literally "singing wolf") and it seems that these place names are due to an elevated presence of wolves at the time of their naming (probably because wolves could be heard howling, but this etymology is actually disputed nowadays).
Cantalupo in Imperial Roman times housed a scattering of villas, one belonging to the Tullii, the family of the orator Marcus Tullius Cicero, but in the Migrations period the inhabitants were protected by a walled castle at the high point of a rocky spur, which was in possession of the counts of Cuneo. Cantalupo was not mentioned however, until an 11th-century register reported the walled village as a possession of the abbots of Farfa. Though in 1278 the comune's representatives swore fealty to the Papacy, its borderlands position in the marches of Lazio (governed from Rome) and Umbria, Cantalupo passed from one feudatory lord to another. The rocca commanding the town was expanded into a residence for the counts of Sant'Eustachio in the 13th and 14th centuries, and then passed to the Savelli family in the 15th century before it was further enlarged by a series of successive holders of the feodo. It is now a museum. The comune preserves its picturesque character.