The two scholars consulted differ on the etymology of this surname. E. Rossoni traces it to the medieval personal name Musaccus, documented in a Pisan deed in which a certain Ranerius Musaccus appears; the transformation into a surname is attested at Conversano in 1709. F. De Laurentiis, by contrast, proposes that the surname originates in a nickname and occupational term derived from musacchino, a word that designated the part of old armor designed to protect the shoulders; as an alternative, De Laurentiis also considers a derivation from the surname Musi. A third possibility is recorded in a separate source, which connects the surname to the Albanian surname Muzachi or to the Greek surname Musakis.

Regarding geographic distribution, Rossoni notes that Musacchi is typical of the area of Ferrara — specifically attested at Argenta and Ferrara — while the variant Musacco is concentrated at Trani and Cerignola, in the area of Bari.