William Gaines (1922–1992) was an American publisher, notably of Mad magazine.
William Gaines may also refer to:
- William E. Gaines (1844–1912), U.S. Representative from Virginia
- William Gaines (professor) (1933–2016), American journalist and professor
- William Gaines (American football) (born 1971), American footballer
- Bill Gaines (basketball) (born 1946), retired basketball guard
- William Gaines (minister and community leader), a freed slave who was a minister and community representative during the Reconstruction Era in Georgia
- Bill Gaines (sprinter), winner of the 60 yards at the 1968 USA Indoor Track and Field Championships