The authors agree that this surname derives from the medieval name Leopardus, linked to the leopard, an animal that in ancient tradition was regarded as a hybrid of lion and panther. E. De Felice notes that the etymological base goes back to the Late and Medieval Latin leopardus, taken from the Greek and Byzantine leopardos, itself compounded from léon ("lion") and párdos ("panther").

De Felice adds that, probably during the early Middle Ages, this word crossed with a personal name of Germanic origin, Lombard and Frankish, formed from the elements leubha- (German lieb: "beloved, dear") and hardhu- ("strong, valiant"), documented from the middle of the 8th century in forms such as Leopardus, Lopardus, Liupard, Lupard and Lepard.

E. Rossoni supplies a concrete documentary testimony: in Pisa, in the year 1400, the form Leopardus condam domini Iacobi del Fornaio is recorded, and he further mentions an earlier example from a Roman tombstone. Rossoni also notes the scattered presence of the surname throughout peninsular Italy, with the greatest concentration in Rome, while the variant Leopardo appears in a much more limited way in the areas of Rome, Naples and Taranto.