B. Zuanella places this surname as typical of Pulfero, a locality of the Natisone valley, in the region of Friuli-Venezia Giulia, from where it spread towards other settlements of the valley —reaching Vernasso in 1845. The original form is not entirely clear: it fluctuates between Mancin, Mansin and Manzin, and the present spelling Manzini became fixed only in the 19th century. Zuanella supposes that the surname could have reached Pulfero from Friuli or Veneto, possibly through public officials who served at the local customs post under the Republic of Venice and who ended up settling there.

As for the semantic origin, Zuanella proposes two hypotheses. The first derives it from the term mancin or manzin, a word meaning "left-handed" both in Friulian and in the Venetan dialect. The second links it to the zoonym manso or manzo —that is, "young bullock"—, from which the diminutive form manzin would have arisen, with an origin in the pastoral sphere to designate whoever tended those animals. At Losaz, belonging to the comune of Savogna, a house name (hišno ime) Manzini —in Slovene, Mandzini— is documented from the middle of the 18th century, derived from the nickname Manzin, although there is no record that the surname as such existed there.

The surname Manzoni —a related form— is held to derive from the Germanic name Manzus and to have its origins in the Valsassina, with a documented presence in various localities of the Lecco area from the 16th century.