He starred in the HBO television series Eastbound & Down and Vice Principals, which he co-created with frequent collaborator Jody Hill, and The Righteous Gemstones, which he created himself.

He has appeared in films such as The Foot Fist Way (2006), Hot Rod (2007), Pineapple Express (2008), Tropic Thunder (2008), Up in the Air (2009), Land of the Lost (2009), Your Highness (2011), This Is the End (2013), and Alien: Covenant (2017).

[14] In 2006, McBride played Fred Simmons in the low-budget comedy film The Foot Fist Way, which he co-wrote with collaborators Jody Hill and Ben Best.

McBride wrote and starred in the HBO original comedy series Eastbound & Down (also a collaboration with Hill and Best), as Kenny Powers, a washed-up former major league baseball pitcher with anger management issues.

The series was produced by Gary Sanchez Productions, and the pilot episode premiered on February 15, 2009, featuring Will Ferrell and Craig Robinson.

In 2017, McBride appeared in the prequel film Alien: Covenant, alongside Katherine Waterston, Michael Fassbender and Billy Crudup.

McBride told Vanity Fair in an interview that he was both surprised and glad for the opportunity to be involved with the Alien movie since he had been a longtime fan of the franchise.

The trailers feature cameo appearances by Australian actors Chris Hemsworth, Hugh Jackman, Russell Crowe, Margot Robbie and Ruby Rose.