E. De Felice notes that this surname derives from the given name Emanuele —or Manuele, with the loss of the initial E-—, documented in Tuscany during the 13th century in the forms Hemanuellus, Manuellus and Manovellus. The name, of Israelite and also Christian tradition, comes from the Latin Emmanuel, an adaptation of the biblical Greek Emmanuél, and this from the Hebrew Immanuel, meaning "God is with us". It is the title with which the prophet Isaiah names the future Messiah.

S. Vannozzi agrees that the surname derives from the proper name Emanuele, of biblical and Christian tradition, and adds that it appears frequently in the variants Manuele and Emmanuele. Vannozzi places its origin in Castelpagano, in the Benevento area, region of Campania, from where it would have been introduced into Cercemaggiore, in the Campobasso area, region of Molise, towards the last decade of the 17th century.