Mancuso is the most common surname in Sicily, and may refer to:
- Alejandro Mancuso, a retired Argentine footballer
- Anna Mancuso, a Canadian former politician
- Ciro Mancuso, a Nevada-based drug dealer convicted of running a $140-million marijuana smuggling operation
- David Mancuso, an American DJ
- Filippo Mancuso, an Italian judge and politician
- Frank Mancuso Jr., a movie producer
- Gus Mancuso, a catcher in Major League Baseball from 1928 to 1945
- Julia Mancuso, an American alpine skier who won a gold medal at the 2006 Winter Olympics
- Laurence Mancuso, founding abbot of the New Skete monastery
- Nick Mancuso, an Italian-Canadian cinema and stage actor
- Salvatore Mancuso, a Colombian paramilitary warlord
- The fictional character Nick Mancuso, played by Robert Loggia in Favorite Son (1988) and Mancuso, F.B.I. (1989)