E. De Felice notes that the surname derives from nicknames formed from the words manco or mancu / mankú, and mancuso or mancusu / mankósu, the equivalents in southern Italy and in Sardinia of "left-handed". He adds that Mancusi or Mancuso, in Campania and in eastern Sicily, may also reflect the place names Mancusi, in the Benevento area, and Mancusa, in the Messina area.

E. Rossoni confirms the origin in the ancestor's trait of being left-handed and supplies early documentation: in the second half of the 13th century, at Afragola, a judicial deed mentions Jacobus Manconus and Petrucius Manconus, which constitutes one of the earliest known traces of its fixing as a surname. Rossoni further specifies the geographical distribution of the variants: Manco shows areas in that of Naples and in the Salento —the southernmost zone of the region of Puglia, in southern Italy—; Mancone appears in the Frosinone, Naples and Puglia areas; Manconi is characteristic of Sardinia; and Mancon, of scarce presence, is located in Veneto.