After numerous appearances as a television guest star, Posehn acquired his first major recurring role in HBO's Mr. Show with Bob and David (1995–1998).

He is known for his roles as Jim Kuback on The WB's Mission Hill and Brian Spukowski on Comedy Central's The Sarah Silverman Program.

He appeared as two different characters in NewsRadio: a fan with questions for Jimmy James at a book reading (1997), and a member of Dave's a cappella group "Chock Full o' Notes" (1998).

He also appeared in the 2005 pilot for The Showbiz Show with David Spade, in a segment called "The Nerd Perspective", in which he gave a scathing criticism of MTV and its declining quality.

Posehn voices the character of Murray, a robot, in Rob Zombie's animated The Haunted World of El Superbeasto.

He participated in the Comedy Lineup of the 2008 Bonnaroo Music and Arts Festival, which included Louis C.K., Janeane Garofalo and Zach Galifianakis.

[12] Posehn countered that "getting a paycheck is metal", and expressed respect towards the Juggalo fan culture, as well as the independent music success of Insane Clown Posse and Psychopathic Records.

Posehn appeared on a Season 4 episode of the music talk show That Metal Show and Lamb of God's Walk With Me In Hell DVD, and performed "More Metal Then You", a song that was included on his non-musical stand-up comedy album Fart & Weiner Jokes, with "Brian Posehn's All-Star Band" on the 2010 Revolver Golden Gods Awards.

In 2020, Posehn released his first music-only album, Grandpa Metal, which featured guest appearances from Brendon Small of Dethklok, Scott Ian, Corey Taylor of Slipknot and Stone Sour, Weird Al Yankovic, Phil Demmel of Machine Head, Michael Starr of Steel Panther and others.

Posehn has provided voice work for video games Brütal Legend as The Hunter[16] and Star Warped as co-narrator Brian.

Posehn appeared in the commercial "Ink Fairy" for Staples office supply store in its ad campaign featuring the "Easy Button."

initiative Posehn and Gerry Duggan co-wrote the Deadpool ongoing comic series which launched in November 2012, lasting 45 issues.

Posehn has also participated in the Dungeons & Dragons campaign Force Grey: Lost City of Omu, hosted by Matthew Mercer.

His first Primetime Emmy nomination in 1998 for Outstanding Writing for a Variety or Music Program was for his writing on Mr. Show with Bob and David, which he shared with crew members Scott Aukerman, Jerry Collins, David Cross, Jay Johnston, Bob Odenkirk, Bill Odenkirk, B. J. Porter, and Dino Stamatopoulos.

[2] For his work on Run Ronnie Run!, Posehn was nominated at the 2003 DVD Exclusive Awards for Best Original Song in a DVD Premiere Movie for "The Golden Rule Song" along with performer Jack Black (with the Joey Cheesy Reunion Band) and fellow lyricists David Cross, Bob Odenkirk, Scott Aukerman, B. J. Porter, and Eban Schletter.