The authors agree that this surname has a Greek origin and derives from the term cefalé (Greek κεφαλή), meaning "head". It is a surname peculiar to Sicily.

F. Miranda notes that the Greek word would have given rise, probably, to a nickname referring to the founder of the lineage —with the sense of "stubborn" or "big-headed"— that over time became a surname. Miranda also proposes a second route of origin: through dialectal modifications, the surname could derive from the place name Cefalù, a locality of the metropolitan area of Palermo whose name goes back to the Greek Kefaloidion ("head, cape"), in allusion to the promontory that characterises that place. According to Miranda, the surname is present in all the provinces of Sicily, with predominance in the Messina area, and has specific and localised areas also in Lazio, Lombardy and Calabria.

V. Blunda confirms the Greek etymology and highlights that this surname shares its etymon with other related forms recorded in Sicily, such as Cefalá, Cefala, Cefalia and Cefalo, differing from them in its particular Italianised spelling.