Church started in the entertainment business as a radio personality and doing voiceover work. A part in an independent film convinced him to move to California to pursue an acting career. He played the part of slow-witted airport mechanic Lowell Mather for six seasons (1990–1995) on the NBC sitcom Wings. He worked in television for two more seasons with a lead role on Ned and Stacey opposite Debra Messing. He has had supporting roles in films such as Tombstone, George of the Jungle, and The Specials. Church often plays villains or comic relief in films, most evident by turns in Tales from the Crypt: Demon Knight and Over the Hedge.

After having small roles in films such as Monkeybone and 3000 Miles to Graceland, he made his directorial debut with Rolling Kansas in 2003. Church later took a break from films and relocated back to his native Texas. He has also done voiceover work in commercials, such as for Merrill Lynch and Icehouse beer.

In 2003, Alexander Payne called him regarding the role of “Jack”, the selfish best friend to Paul Giamatti's character, in Sideways. During the audition, Church stripped naked to read the audition scene, later saying “To me it was painfully obvious… I was reading the scene where Jack comes in naked and there has to be in-born vulnerability in the scene.” (He later found that he was the only actor to strip down for the audition). Sideways earned acclaim for Church, for which he won an IFP Independent Spirit Award and was nominated for the Academy Award for Best Supporting Actor.

He has since appeared in films such as Idiocracy, done voice-over work on films such as Over the Hedge and starred in one of AMC's highest rated television productions, Broken Trail, with Robert Duvall, in 2006, for which he won an Emmy. In 2007, he appeared as the villain Sandman in Sam Raimi's Spider-Man 3 starring Tobey Maguire and Kirsten Dunst.

In 2005, he was invited to join the Academy of Motion Picture Arts and Sciences. On September 16, 2007, he won an Emmy Award for Outstanding Supporting Actor in a Miniseries or Movie for his role of Tom Harte on AMC's Broken Trail.

In October 2008, Church appeared in a video on funnyordie.com taking on the role of the fictitious average American, Joe Six Pack, made famous in the 2008 Presidential campaign by John McCain and Sarah Palin. The video titled “Thomas Haden Church vs Joe the Plumber” has Joe Six Pack (Church) taking on his blue collar rival, Joe the Plumber. Church stars also in the FEARnet webseries Zombie Roadkill alongside David Dorfman and under the direction from producer David Green.