The surname Mancini derives from the old Italian nickname mancino, meaning "left-handed" or "one who uses the left hand." In earlier times, this physical trait was distinctive enough to generate a byname, and in rural or traditional societies it could carry symbolic, social, or even religious connotations.

Drawing on the studies referenced in the sources, E. De Felice identifies mancino as a nickname widely used throughout Italy, from which a cluster of surnames developed: Mancini, Mancinelli, and Mancino. The suffix -ini most likely points to a patronymic or affective origin — that is, "son of" or "descendant of" a person called Mancino.

E. Rossoni and J. Tosti classify Mancini as a descriptive surname formed from a physical characteristic, noting its broad distribution across Italy with a particular concentration in central Italy. M. Alinei and F. Benozzo add that in traditional rural culture, left-handedness could hold a symbolic charge — whether positive or negative — and that this cultural weight contributed to the term's becoming fixed as a hereditary surname.

P. Lastrico likewise places Mancini among surnames derived from physical or functional traits and notes its presence in medieval records. The surname is particularly widespread in Lazio and is also found in Tuscany, Umbria, and other central and southern regions of Italy. Related forms include Mancino, Mancina, Mancin, and Mancinelli.