William O'Brien can be:
- William O'Brien (1852–1928), Irish journalist and politician.
- William Smith O'Brien (1803–1864), Irish revolutionary
- Bill O'Brien (born 1929), English Labour MP for Normanton 1983–2005
- Bill O'Brien (American football) (born 1969), offensive assistant coach for the New England Patriots
- William X. O'Brien (1881–1968), founder of the Irish Transport and General Workers' Union
- William J. O'Brien, inventor of the Decca Navigator System.
- William O'Brien, 4th Earl of Inchiquin, 9th Baron Inchiquin, founder of the Royal Cork Yacht Club.
- William J. O'Brien (1836–1905), Congressional Delegate from Maryland (3rd District), United States House of Representatives, 1873–1877
- Parry O’Brien (1932-2007), American shot-put innovator
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