Tompkins was the voice of Mr. Peanutbutter, an anthropomorphic yellow labrador, on the Netflix animated series BoJack Horseman from 2014 to 2020.

[3][6] Tompkins deals with topics of the bizarre and the absurd[3][4]—such as a rant about peanut brittle,[6][21] a discussion about cake versus pie,[21] and smashed coins[6]—in addition to recounting stories about his own life experiences and family.

[3][17][18][21] His comedic style has been described as alternative comedy;[10][21][22] Tompkins has stated that he is not bothered by the label and that he likes the term.

[3][26][27] His show has featured such guests as Fiona Apple, Jack Black, Dave Foley, Zach Galifianakis, Ed Helms, Aimee Mann, and Weird Al Yankovic.

[3] Since its inception in 2005, Tompkins has taken part in the Thrilling Adventure Hour, a staged production in the style of old-time radio that is also held monthly at Largo.

[33] He also performs monthly at the "Dead Authors" show at UCB Theatre in support of the nonprofit organization 826LA;[34][35] Tompkins plays the role of H.G.

[34] Tompkins has toured in the US and Canada[36] and prefers to perform in independent venues, rather than conventional comedy clubs.

[9][25][38] Bob Kerr, a Canadian comedian, saw the Twitter post and asked if Tompkins would like to perform in Toronto.

Kerr then started a Facebook group called "I Wanna See Paul F. Tompkins in Toronto" and managed to get 300 people to join.

[25][40] Facebook groups were subsequently started in other North American cities[25] and in 2010 he stated that he had stopped promoting his shows on the radio.

[4] Tompkins's work with Mr. Show's creators Bob Odenkirk and David Cross also led to his recurring role on the Tenacious D TV series.

[10][17] Tompkins played the character of a nightclub manager who is duped into reading Tenacious D's ridiculous introductions during their open mic performances.

[10] Tompkins also played the MC of a cat show in McKay's Anchorman: The Legend of Ron Burgundy.

[15][17] In 2011 Tompkins was asked to write humorous recaps of American Idol episodes for New York magazine's online blog Vulture.

He lent his voice to a character in an unaired 2007 episode of Aqua Teen Hunger Force titled "Boston" that was supposed to be the premiere episode of the show's fifth season, but it was pulled by Turner Broadcasting System to avoid further controversy surrounding the 2007 Boston bomb scare.

In 2020, he voiced Dr. Migleemo, a therapist aboard the USS Cerritos in the CBS All Access animated series Star Trek: Lower Decks.

[5][6][12] In 2008 he appeared on Lewis Black's Root of All Evil[35][52] and took part in a panel on Larry King Live in an episode titled "Politics & Humor".

Tompkins has appeared in documentaries such as Jamie Kennedy's Heckler (2007) and Doug Benson's Super High Me (2007).

Dead Authors, a live show that Tompkins hosts at the UCB Theatre in Los Angeles, also began podcasting in September 2011.

Hosted by the Break Media site MadeMan.com, the series features Tompkins interviewing various guests in the entertainment industry, such as Ty Burrell, Nathan Fillion, Zach Galifianakis, Chris Hardwick, Oscar Nunez, Weird Al Yankovic, and Alison Brie.

(formerly Comedy Death-Ray Radio),[5][22][25] a weekly audio podcast hosted by Scott Aukerman, a comedian who also wrote for Mr. Show with Bob and David.

Some guests play characters or impersonate certain celebrities, usually for the entirety of the episode; Paul F. Tompkins has impersonated celebrities such as rapper Ice-T, composer Andrew Lloyd Webber, and Buddy Valastro from the reality television series Cake Boss (cakeboss.).

Spontaneanation begins with an improvised monologue, accompanied on piano by Eban Schletter, much like the Pod F. Tompkast.

Along with Tawny Newsome, he also hosts The Pod Directive, the official Star Trek podcast, which launched in September 2020.

[68] He is a member of the Democratic Socialists of America and helped canvass for Eunisses Hernandez and Hugo Soto-Martinez during the 2022 Los Angeles elections.