Reilly, the fifth of six children, was born in Chicago, Illinois to an Irish American father and a Lithuanian mother. His father owned a linen supply company. He was raised in the Catholic religion and graduated from Brother Rice High School. Reilly had several minor infractions for juvenile mischief. To better occupy his time, he later became involved with theatre. He subsequently enrolled at the Goodman School of Drama at DePaul University. A proud member of the Chicago theater, Reilly credits the Windy City with helping him gain experience as he was working for his big break.

He has been married since 1992 to Alison Dickey, whom he met on the set of Casualties of War.

Reilly made his film debut in the Brian De Palma film Casualties of War (1989) as PFC Herbert Hatcher. Although the role of Hatcher was written as a small one, De Palma liked Reilly's performance so much that the role was significantly expanded.

Reilly has consistently appeared in film since his debut; he has appeared in an about 50 roles since 1989, mostly supporting roles. In the past six years, he has been a friend of Tenacious D, appearing as "Sasquatch" in the late-nineties HBO television show Tenacious D, on their 2001 album Tenacious D, and in the 2006 feature-length movie, Tenacious D in: The Pick of Destiny.

His profile as a film actor was significantly raised in 2002 when he appeared in three of the year's Academy Award for Best Picture nominees - Chicago, Gangs of New York and The Hours. The three movies were nominated for a total of 32 Oscars, including one for Reilly for an Academy Award for Best Supporting Actor for his performance as Renée Zellweger's trusting husband in Chicago. Ultimately, Gangs of New York won none, Chicago won six, and The Hours won one. Reilly lost to Chris Cooper for Adaptation..

More recently, Reilly appeared in the Martin Scorsese film The Aviator (2004) as Howard Hughes's (Leonardo DiCaprio) trusted financial advisor, Noah Dietrich. Reilly had to turn down the role of Champ Kind in the Will Ferrell film Anchorman: The Legend of Ron Burgundy in order to appear in The Aviator.

Reilly has been praised for his diversity as an actor, drawing plaudits for his dramatic roles, and also for being a great comedic actor with notable roles in Talladega Nights: The Ballad of Ricky Bobby and his most recent movie, Walk Hard.

He is also a singer, performing on two tracks of the 2006 compilation Rogue's Gallery: Pirate Ballads, Sea Songs, and Chanteys: Fathom the Bowl and My Son John.

He also performed his own vocals in "Walk Hard," and went on tour in the US, performing as Dewey Cox in the "Cox Across America 2007 Tour."

Most recently he has appeared in adult swim's Tom Goes to the Mayor and Tim and Eric Awesome Show Great Job!. In May 2008 he appeared as part of T&E's Awesome Tour 2008 the Echoplex in Los Angeles.

Provided the voice of himself in The Simpsons episode Any Given Sundance.

Reilly is also very good friends with Paul Thomas Anderson.Reilly is a Vegetarian and resides in Los Angeles.

• Casualties of War(1989) as PFC. Herbert Hatcher
• We're No Angels (1989) as Young Monk
• Days of Thunder(1990) as Buck Bretherton
• State of Grace(1990) as Stevie McGuire
• Shadows and Fog(1992) as Cop at Police Station
• Out on a Limb(1992) as Jim Jr.
• Hoffa(1992) as Pete Connelly
• What's Eating Gilbert Grape(1993) as Tucker Van Dyke
• The River Wild(1994) as Terry
• Dolores Claiborne (1995) as Const. Frank Stamshaw
• Georgia(1995) as Herman
• Hard Eight (1996) as John Finnegan
• Boys (1996) as Officer Kellogg Curry
• Nightwatch (uncredited) (1997) as Deputy Inspector Bill Davis
• Boogie Nights(1997) as Reed Rothchild
• Hellcab (1998) as Steve
• The Thin Red Line(1998) as Sergeant Storm
• The Settlement(1999) as Pat
• Never Been Kissed(1999) as Augustus Strauss
• For Love of the Game(1999) as Gus Sinski
• Magnolia(1999) as Jim Kurring
• The Perfect Storm(2000) as Dale 'Murph' Murphy
• The Anniversary Party(2001) as Mac Forsyth
• The Good Girl (2002) as Phil Last
• Gangs of New York(2002) as Happy Jack
• Chicago (2002) as Amos Hart
• The Hours(2002) as Dan Brown
• Anger Management(2003) as older monk Arnie Shankman
• Piggie(2003)
• The Aviator(2004) as Noah Dietrich
• Criminal(2004) as Richard Gaddis
• Dark Water(2005) as Mr. Murray
• A Prairie Home Companion (2006) as Lefty
• Talladega Nights: The Ballad of Ricky Bobby(2006) as Cal Naughton, Jr.
• Tenacious D: The Pick of Destiny(2006) as Sasquatch (uncredited)
• Year of the Dog(2007) as Al
• Walk Hard: The Dewey Cox Story (2007) as Dewford "Dewey" Cox
• The Promotion ]](2008) as Richard
• Step Brothers ]](2008) as Dale Doback

• 9 (2008) (voice only) (post-production)
• Cirque du Freak (2009) as Larten Crepsley (post-production)