Mancuso is an Italian surname derived from a Sicilian noun, related to the Italian mancino, which means "left-handed". An alternate form can be Mancusi. Notable people with the surname include:

• Alejandro Mancuso, retired Argentine footballer
• Anna Mancuso, Canadian former politician
• Ciro Mancuso, Nevada-based drug dealer convicted of running a $140-million marijuana smuggling operation
• David Mancuso, American DJ
• Filippo Mancuso, Italian judge and politician
• Francis Xavier Mancuso, Leader of Tammany Hall and a judge for New York's Court of General Sessions
• Frank Mancuso Jr., movie producer
• Gus Mancuso, catcher in Major League Baseball from 1928 to 1945
• Julia Mancuso, American alpine skier who won a gold medal at the 2006 Winter Olympics
• Laurence Mancuso, founding abbot of the New Skete monastery
• Leonardo Mancuso, Italian footballer
• Nick Mancuso, Italian-Canadian cinema and stage actor
• Renee Mancuso, American bridge player
• Rudy Mancuso, American actor and Internet personality and musician
• Salvatore Mancuso, Colombian paramilitary warlord
• The fictional character Nick Mancuso, played by Robert Loggia in Favorite Son (1988) and Mancuso, F.B.I. (1989)
• The fictional character Angelo Mancuso in the novel A Confederacy of Dunces (1980)
• The fictional character Bart Mancuso, played by Scott Glenn in The Hunt for Red October (1990)