Reilly gained prominence for his roles in comedy films such as Cal Naughton in Talladega Nights: The Ballad of Ricky Bobby (2006). He then went on to play the title character in Walk Hard: The Dewey Cox Story (2007) and Dale Doback, one of the two stepbrothers, in Step Brothers (2008). Meanwhile, Reilly began co-starring as Dr. Steve Brule in the comedic television series Tim and Eric Awesome Show, Great Job! (2007–2010), which led to the spin-off series Check It Out! with Dr. Steve Brule (2010–2016). He voiced the title character in the Wreck-It Ralph film series (2012–2018). Reilly is also known for his work in the independent films Cyrus, We Need to Talk About Kevin, and Carnage (all in 2011), The Lobster (2015), and The Sisters Brothers (2018). He combined his comedic and dramatic abilities for his portrayal of comedian Oliver Hardy in the biopic Stan and Ollie (2018), earning nominations for the Golden Globe Award and Critics' Choice Award.
Reilly is also known for his work on television. He created and starred in the Showtime comedy series Moonbase 8 (2020) and led an ensemble cast for the HBO sports drama series Winning Time: The Rise of the Lakers Dynasty (2022–2023). Reilly performs with his band, John Reilly and Friends. For his role in the Broadway revival of Sam Shepard's play True West (2000), he was nominated for the Tony Award for Best Actor in a Play.
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