After graduating, he worked as the musical director of the Pheasant Run Theater, composed original music for a Steppenwolf production of "Antigone" and joined the famed improv group Second City, where he honed his comedic skills. Stints as a stand-up comic and appearances in national TV commercials as well as occasional guest shots followed. Hayes landed the leading role of a gay photographer, an incurable romantic, who develops a crush on one of his model in "Billy's Hollywood Screen Kiss". Managing to be both endearing and self-deprecating, he proved a charming center to the fluffy comedy. Spotted by a casting agent at the Sundance screening, Hayes was offered the role of Jack McFarland, the self-centered gay best buddy of attorney Will Truman (Eric McCormack), in "Will & Grace". Almost immediately, through his gleeful and outlandish performance, he became one of the show's most popular figures, milking laughs from his encounters with Karen (Megan Mullaly). Hayes netted a 2000 Emmy Award for Outstanding Supporting Actor in a Comedy Series and earned five more consecutive Emmy nominations, as well as three Screen Actors Guild Awards for Outstanding Performance by a Male Actor in a Comedy Series in 2002, 2003 and 2006 in the process.

He was then cast as comic great Jerry Lewis, an equally wisecracking actor, in the CBS biopic "Martin and Lewis" (2002) a made-for-television movie followed the volatile relationship between Lewis and his partner Dean Martin. Hayes came as close to capturing Lewis' spastic energy as any actor could be expected to, but his performance was weighed down by the heavy-handed storytelling and an absence of chemistry with miscast co-star Jeremy Northam. Hayes dialed down the antics tremendously but still delivered a spot-on comedic performance when he played a repressed, uptight New Yorker who tangles with his neighbor (Katie Holmes) in the digital film "Pieces of April" (2003). That same year Hayes was repressed and uptight again as he voiced the computer generated Fish in the live-action version of "Dr. Seuss' The Cat in the Hat"--he also pulled double-duty in the film, playing the germophobic Mr. Humberfloob.