The authors agree that this surname derives from the place name Perugia, a city of the region of Umbria. E. De Felice and E. Rossoni note that it comes from the medieval name Perusinus, a hypocoristic of Perusius, used as a demonym to refer to the inhabitants and natives of Perugia and its territory. The suffix -ini, characteristic of the onomastics of central Italy, combines a demonym value —"the one from Perugia"— with a patronymic value —"of the family of the Perugini"—, giving rise to the sense of "descendant of the family originating from Perugia."

As to geographic distribution, De Felice and Rossoni indicate that the surname is concentrated in central Italy, especially in Umbria, Tuscany and Lazio, with presences also in the Marche, Emilia-Romagna and the north of the country. In line with this, Perugini is held to be the most widespread form of the group, with a presence in Romagna, Tuscany, the Marche, Umbria and Lazio.

The set of related variants —Peruggini, Perugina, Perugino, Perugi, Peruselli, Perusi, Perusini, Perusino— shares the same toponymic base, although some could also derive from the medieval name Perusius or from hypocoristic forms such as Perusinus. It is recorded that Peruggini is typical of Naples; Perugino appears in Campania, Calabria and Apulia; Perusi is located in the Verona area; and Perusini seems proper to Friuli, in particular to the Udine area.