McBride was born in Statesboro, Georgia and raised in Fredericksburg, Virginia, where he attended Courtland High School. In 2006, he played one of the lead roles in the low-budget comedy film The Foot Fist Way, which he wrote with friends and frequent collaborators Jody Hill and Ben Best. McBride appeared as a guest on Late Night with Conan O'Brien on February 26, 2008 as the character Fred Simmons of The Foot Fist Way.

McBride has appeared in supporting roles in the comedy films Hot Rod, The Heartbreak Kid, Pineapple Express, Tropic Thunder, Observe and Report, and Your Highness. He created and stars in the HBO sitcom Eastbound & Down, about a washed up former major league baseball player with anger management issues, also a collaboration with Hill and Best. The teachers that appear in the series are teachers that McBride actually had in high school. The name of the middle school that McBride's character teaches at in the series comes from a local highway in Fredericksburg, Virginia (Jefferson Davis Highway). The series is produced by Gary Sanchez Productions and the pilot episode premiered February 15, 2009. It features guest appearances from frequent collaborators Will Ferrell and Craig Robinson. On April 8, 2009, HBO announced it had renewed the series for a second season. In March 2009, McBride was offered a contract to play professional baseball with the Pensacola Pelicans, a minor league team in the American Association of Independent Professional Baseball. He received the offer for his role as Kenny Powers, a washed up former major league pitcher, on HBO's Eastbound & Down. In addition, in 2010 he signed an endorsement deal with K-Swiss shoes, again performing in character as Powers.