William H. Macy was born in Miami to a World War II pilot. In 1971 he moved to Chicago, where he became close with playwright David Mamet. He worked at a Chicago theater founded with Mamet, and in 1985 he settled with him in California, where he was one of the founders of Mamet's new troupe, the Atlantic Theatre Company.

After episodic appearances on the big screen in such films as Radio Days (1987) and The Client (1993), Macy was cast in a supporting role in the Coen brothers' acclaimed tragicomedy Fargo (1996). Due to the success of that film, he was invited in 1997 to appear in several notable films, including Wag the Dog, Air Force One, Psycho, and Boogie Nights.

Among Macy's subsequent films are Magnolia (1999), Cellular (2004), and Wild Hogs (2007). In the 2000s, Macy also took part in several television projects, for which he was twice awarded the Emmy in 2003. In particular, he appeared in the popular television series ER (1994–1998).