He gained exposure through his supporting roles in Tony Scott's Days of Thunder (1990), Paul Thomas Anderson's films Hard Eight (1996), Boogie Nights (1997) and Magnolia (1999), and Martin Scorsese's Gangs of New York (2002) and The Aviator (2004).

Meanwhile, Reilly began co-starring as Dr. Steve Brule in the comedic television series Tim and Eric Awesome Show, Great Job!

[25] His next role was in The River Wild (1994), in which Reilly appeared alongside Kevin Bacon as a pair of criminals who terrorise a family during a rafting trip.

[26] In 1995, Reilly appeared in the psychological thriller Dolores Claiborne as a police constable and in the drama Georgia as a drug-addicted drummer in the band Jennifer Jason Leigh's character joins.

[27][28] In Paul Thomas Anderson's directorial debut film Hard Eight (1996), Reilly played a near homeless man in Reno, Nevada, who is taken under the wing of a senior gambler (Philip Baker Hall).

[18][29] Reilly collaborated with Anderson on other films, playing a pornographic actor in Boogie Nights (1997);[18] a deeply religious police officer in Magnolia (1999);[17][18] and a cameo in the music video for Fiona Apple's single "Across the Universe".

[30] Terrence Malick's ensemble war film, The Thin Red Line (1998) featured Reilly in a supporting role that was written as a larger one, but much of his scenes were deleted along with many other cast members.

[31] In 1999, Reilly starred in the independent film The Settlement alongside William Fichtner, which Variety writer Robert Koehler dismissed as a "write-off" despite praising his performance.

[33] In Sam Raimi's sports drama For Love of the Game, released the same year, Reilly played fictional baseball catcher Gus Sinski.

[18][38][39] Zellweger remarked that "John is so often the best thing about the movies he's in" and critic Roger Ebert praised the "pathetic sincere naivete" that Reilly brought to the role.

[40][41] Martin Scorsese's Gangs of New York featured Reilly as corrupt 19th-century constable "Happy Jack" Mulraney, while Stephen Daldry's drama The Hours saw him play the husband to Julianne Moore's character.

Based on the Argentine film Nine Queens (2000), Stephen Holden of The New York Times felt that "John C. Reilly may be one of our finer character actors, but his portrayal of Richard Gaddis, a gimlet-eyed con man, in Criminal allows too many vestiges of the duped schlub of a husband he played in Chicago to leak into his performance.

[47] Reilly co-starred in Adam McKay's comedy about NASCAR drivers entitled Talladega Nights: The Ballad of Ricky Bobby in August 2006 as Cal Naughton Jr., the best friend and teammate of the title character, played by Will Ferrell.

New York Daily News critic Elizabeth Weizxman considered Reilly a stand out in the film and he received an Independent Spirit Award for Best Supporting Male nomination.

[63] Reilly co-starred alongside Ezra Miller and Oscar-winner Tilda Swinton in the British-American drama We Need to Talk About Kevin, based on the novel by Lionel Shriver.

It also starred Oscar-winners Jodie Foster as his wife, and Kate Winslet and Christoph Waltz as another married couple who engage in a conflict after their children get into a fight.

[67] Reilly was approached to appear in a production of the play it was based on, God of Carnage, but he couldn't fit it into his schedule and remarked "I think I've spent enough time in that apartment".

[68] Reilly voiced the title character in the 2012 animated film Wreck-It Ralph,[69] which follows an arcade game villain who is determined to prove himself as the hero.

[70] The film was positively received,[71] with Los Angeles Times writer Betsy Sharkey saying, "The movie's subversive sensibility and old-school/new-school feel are a total kick.

[76][77] He had a cameo in the 2013 comedy sequel Anchorman 2: The Legend Continues, playing the ghost of Confederate General Stonewall Jackson in the film's fight scene.

[81][82] 2015 saw him appear in five films: the drama Entertainment;[83] Yorgos Lanthimos' comedy-drama The Lobster as Robert, a man with a lisp who is given 45 days to find a romantic partner or otherwise be turned into an animal;[84] the fantasy horror Tale of Tales, in which he played a king who tries to conceive a child with his queen–played by Salma Hayek–through an unconventional method,[85] and the English dub of the Studio Ghibli animated film When Marnie Was There.

The first single features two The Delmore Brothers songs: "Gonna Lay Down My Old Guitar" and "Lonesome Yodel Blues #2", both performed with Tom Brosseau.

[112] In 2022, he sang the Percy French-composed song "Eileen Óg" with singer and button accordion player Séamus Begley on the Irish traditional band Téada's album "Coiscéim Coiligh /As the Days Brighten.

He and co-star Philip Seymour Hoffman (after starring in Hard Eight and Boogie Nights) were both nominated, alternating between the two lead characters during separate performances.

[118] In March 2012, he was featured in a performance of Dustin Lance Black's play, 8—a staged reenactment of the federal trial that overturned California's Prop 8 ban on same-sex marriage—as David Blankenhorn.

[119] The production was held at the Wilshire Ebell Theatre and broadcast on YouTube to raise money for the American Foundation for Equal Rights, a non-profit organization funding the plaintiffs' legal team and sponsoring the play.