He has also worked in films such as X-Men Origins: Wolverine (2009), Battleship (2012), John Carter (2012), Savages (2012), Lone Survivor (2013), The Grand Seduction (2014), American Assassin (2017), Only The Brave (2017), and 21 Bridges (2019).

[14] In 2006, Kitsch was cast in his breakout role on the NBC sports teen drama television series Friday Night Lights, based on Peter Berg's 2004 film of the same name and set in the fictional town of Dillon, Texas.

For five seasons Kitsch portrayed the role of Tim Riggins, a high school student who is the fullback/running back of the Dillon Panthers.

[17] He played Pogue Parry in The Covenant, alongside Steven Strait, Sebastian Stan, Laura Ramsey, Toby Hemingway, Jessica Lucas, and Chace Crawford.

[19] He had to lose 35 pounds in two months to play the role of photojournalist Kevin Carter, alongside Ryan Phillippe and Malin Åkerman.

"[23] In May 2012, Kitsch starred in Peter Berg's Battleship, based on Hasbro's toy game, as Lieutenant Alex Hopper.

McWeeny wrote that Kitsch was used the right way in this film with an ensemble cast that pushed him or challenged him in scenes which resulted in his playing them with appropriate intensity.

[28] He plays alongside Jim Parsons, Julia Roberts, and Mark Ruffalo in Ryan Murphy's The Normal Heart, which aired on HBO on May 25, 2014.

Kitsch starred in the sophomore season of True Detective, opposite Vince Vaughn, Rachel McAdams, and Colin Farrell.

He was tapped to replace Colson Baker, better known as Machine Gun Kelly, in the film Savage Salvation, where he would have starred alongside Robert De Niro and John Malkovich.

In early 2021, it was announced that Kitsch would star as Ben Edwards opposite Chris Pratt in Antoine Fuqua's The Terminal List.

[34] While collaborating on the film Lone Survivor, he became close to retired Navy SEAL Marcus Luttrell and has since been focused on veterans’ issues.