The three scholars consulted — F. Miranda, A. Bongioanni, and G. P. Holmes — agree that this surname derives from the Latin lupus ("wolf"), with roots that reinforced one another over the course of history. Miranda notes that it continues the late Latin cognomen Lupus and was consolidated in the early Middle Ages through the influence of Germanic names built on the root wolff, as well as the Lombard personal names Lupo and Lupone, used to identify strong men, the wolf being a symbol of strength. Bongioanni adds that in Roman onomastics the wolf was an almost sacred animal — it was the she-wolf who nursed the founders of Rome — and that in the Germanic tradition the wolf (wulf) held a central place as a symbol of valor. Holmes likewise emphasizes both the Roman and the Germanic dimensions of the name.

Bongioanni further proposes a third etymology: the Lombard forms Lupo and Lubo would derive from the root luba or liuba, carrying the meaning of "to love" and "love." He also notes the existence of a Saint Lupus, bishop of Bergamo, who died in the year 300 and is celebrated on June 9, whose cult may have reinforced the spread of the personal name. It is also recorded as a nickname meaning "wolf." Among the derived forms, Bongioanni lists Lupi, Lupati, Lupini, Luporini, Lovati, Lubatti, Luotto, and Lovera, among others.

The surname has multiple independent ancestral stocks (ceppi), arising in different regions with no direct connection between them. Miranda notes that it is found throughout Italy, with a particularly marked presence in Sicily, Apulia, and Lombardy, and is also frequent in Piedmont, Campania, Lazio, Tuscany, Calabria, Liguria, and Basilicata. Among the variants he records are Lupis, Luppis, Lupelli, Lupetti, Lupatti, Lupini, Luperini, and Lupone.