Trivia: His best friends called him "Willie" when he attended Bethany College in Bethany, West Virginia Studied under David Mamet at Goddard College, Vermont. Was a founding member of St. Nicholas Theater in Chicago with David Mamet and writer Steven Schachter. While in New York, worked as "voice-over talent", including "Secret - strong enough for a man but made for a woman" ("That's my most famous voice-over"). (Esquire, August 1997). Uses the name William H. Macy so he won't be confused with 1970s comedian Bill Macy. He, wife Felicity Huffman, Giancarlo Esposito and TV stars Camryn Manheim and Kristen Johnston are all members of the New York-based Atlantic Theater Company.

He and his wife Felicity Huffman welcomed their first child, Sofia Grace, on August 1, 2000. Daughter Georgia Grace born 14 March 2002 in Los Angeles. The writers and producers of "The Simpsons" (1989) have joked semi-seriously that if there was ever a live action version of the show, then he would be the perfect choice to play Ned Flanders. Remembers jokes and always tells one when he appears on "Late Night with Conan O'Brien" (1993). Was the first choice to voice Marlin in Finding Nemo (2003). In 1985, he and David Mamet co-founded the Atlantic Theater Company, located in New York, New York, USA. His agent tried to discourage him from reading the script for Boogie Nights (1997), but he read it anyway, loved it, and signed on to do the film. Became a spokesperson for United Cerebral Palsy after filming Door to Door (2002) (TV).

His father lives in Gainesville, Florida. Has admitted to experimenting with LSD in college. William stated some friends referred to him as "acid head". He attended Allegany High School in Cumberland, Maryland. He was junior and senior class president of his graduating class. The pop rock band Head Automatica has a song named after the actor called "I Shot William H. Macy" Met Felicity Huffman when she was one of his students at the Atlantic Theater Company He and wife Felicity Huffman both received Emmy-nominations in 2005 After spending years in Chicago theater and building his resume as an actor, at age 28 he relocated to New York City for film and television work. Auditioned for the role of "Brian" on "Family Guy" (1999). Was among the guests at Marcia Cross' wedding to Tom Mahoney