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He also runs a television production company called Hazy Mills Productions, which produces shows such as Grimm, Hot in Cleveland, The Soul Man, and Hollywood Game Night. He portrayed Jerry Lewis in the CBS film Martin and Lewis (2002). He is known for his appearances in films such as Billy's Hollywood Screen Kiss (1998), Cats & Dogs (2001), Pieces of April (2003), The Cat in the Hat (2003), Win a Date with Tad Hamilton! (2004), The Bucket List (2007), Igor (2008), The Three Stooges (2012), Monsters University (2013), and Am I OK? (2022). Since July 2020, he has co-hosted the comedy podcast SmartLess alongside Jason Bateman and Will Arnett.

Hayes made his Broadway debut playing Chuck Baxter in the musical revival Promises, Promises in 2010, for which he was nominated for the Tony Award for Best Leading Actor in a Musical. He portrayed God in the comedy An Act of God from 2015 to 2016. Oscar Levant in the Doug Wright play Good Night, Oscar in 2022, the latter of which earned him the Tony Award for Best Leading Actor in a Play. He hosted the 64th Tony Awards in 2010, for which he was awarded a Primetime Emmy Award.