DeStefano is an Italian surname with Greek origin. People with the surname include:
- Anthony DeStefano (born 1965), American author
- Chris DeStefano, American singer
- Frank DeStefano, medical researcher
- Fred DeStefano (1900–1974), American football player
- Joe DeStefano (born 1960), politician
- John DeStefano (disambiguation), several people
- Lauren DeStefano (born 1984), American author
- Mario Anthony DeStefano (1915–1975), American gangster
- Mike DeStefano (born 1966), American comedian
- Robert DeStefano (born 1962), American chiropractor
- Stephen DeStefano (born 1966), American comics artist