Paul Francis Tompkins was born September 12, 1968 in Mount Airy, Philadelphia, Pennsylvania. He has two brothers (one older, one younger) and three sisters (all older).

In 1986 Tompkins first performed comedy at 17 years of age at The Comedy Works in Philadelphia (a club now located in Bristol, Pennsylvania) where he performed as half of a Sketch comedy duo with the late Rick Roman. Tompkins attended Temple University; however, he dropped out and left for Los Angeles, California in 1994.

Tompkins wrote for and performed on Mr. Show with Bob and David from 1995 to 1998; the show's Writers, including Tompkins, were nominated for an Emmy Award in 1998 for "Outstanding Writing for a Variety or Music Program".

Tompkins met actor Jay Johnston in L.A. through their mutual friend, actor and Director Adam McKay. McKay and Tompkins had become friends in Philadelphia, where they had both started to perform stand-up at around the same time. McKay later moved to Chicago and met Johnston; Johnston moved to L.A. at around the same time as Tompkins and McKay introduced the two. Tompkins and Johnston went on to create a live Sketch comedy show called "The Skates" that was seen by Bob Odenkirk and David Cross and helped get them hired to work on Mr. Show with Bob and David in 1996.

Tompkins was a contributor to the "Us People's Weekly Entertainment" segment of The Daily Show in 1998. In 2003 he was a Writer and correspondent for Real Time with Bill Maher in the show's first season and wrote again for the show in 2009. He appeared on Tough Crowd with Colin Quinn in 2004. In 2004 he also became a pop culture analyst on VH1's Best Week Ever; in 2008 the show was retooled and relaunched as Best Week Ever with Paul F. Tompkins with Tompkins as host. From 2006 to 2008 he was a regular guest on Countdown with Keith Olbermann. In 2008 he appeared on Lewis Black's Root of All Evil and took part in a panel on Larry King Live in an episode titled "Politics & Humor".

Tompkins is based in Los Angeles and performs regularly in the city. Since 2002 he has performed a monthly show called The Paul F. Tompkins Show at Largo, an L.A. nightclub and cabaret. His show has featured such guests such as Fiona Apple, Jack Black, Dave Foley, Zach Galifianakis, Ed Helms, Aimee Mann, and Weird Al Yankovic. 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. The show began podcasting in January 2011; in October of that same year the show's podcasts moved to the Nerdist Industries podcast network created by Chris Hardwick. Tompkins is a member of the Upright Citizens Brigade Theatre (UCB) Los Angeles. His comedy album "Impersonal" was recorded live at the UCB Theatre. He also performs monthly at the "Dead Authors" show at UCB Theatre in support of the nonprofit organization 826LA; Tompkins plays the role of H.G. Wells who serves as the host of the show.

Tompkins has appeared in documentaries such as Jamie Kennedy's Heckler (2007) and Doug Benson's Super High Me (2007). He also appeared in The Bitter Buddha (2013), a documentary about the career of actor and Comedian Eddie Pepitone.

Tompkins has toured in the US and Canada and prefers to perform in independent venues, rather than conventional comedy clubs. Starting in 2009 he embarked on his "Tompkins 300" tour; Tompkins had been preparing for his one-hour Comedy Central special You Should Have Told Me at the Laughing Skull Lounge theatre in Atlanta, Georgia—a small theatre that seats about 74 people. In order to fill the seats for the recording of his special, Tompkins required about 280 people in the audience over the course of four nights for the recording of his show. Tompkins decided to announce on Twitter that he needed 300 people to fill the seats each night; Bob Kerr, a Canadian Comedian, saw the Twitter post and asked if Tompkins would like to perform in Toronto. Tompkins advised Kerr that if he was able to get 300 people to state that they would definitely see his show he would come to Toronto. Kerr then started a Facebook group called "I Wanna See Paul F. Tompkins in Toronto" and managed to get 300 people to join. In October of that same year Tompkins performed at The Rivoli theatre in Toronto, the same theatre in which the Sketch comedy troupe The Kids in the Hall got their start. Facebook groups were subsequently started in other North American cities and in 2010 he stated that he had stopped promoting his shows on the radio. In 2011 he said that the Facebook 300 groups had become his main method of booking comedy shows.

In 2010 Tompkins launched his podcast called The Pod F. Tompkast. The podcast was a mixture of Tompkins discussing various topics, clips from his live show at Largo, and segments where Tompkins voices a variety of celebrities speaking with one another. Comedian Jen Kirkman was a regular contributor on the show. The podcast ended in 2012.

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

In May 2012 Tompkins started a weekly web series called Speakeasy. 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. The interviews are conducted as Casual conversations between Tompkins and his guests over cocktails at various bars in the L.A. area.

Tompkins stand-up comedy performances are of a storytelling and observationalist style. His shows often consist of extended riffs and long anecdotes. Tompkins deals with topics of the bizarre and the absurd—such as a rant about Peanut brittle, a discussion about cake versus pie, and smashed coins—in addition to recounting stories about his own life experiences and family. His comedic style has been described as alternative comedy; Tompkins has stated that he is not bothered by the label and that he likes the term.

In 2015, Tompkins created his own podcast on the Earwolf podcast network called Spontaneanation with Paul F. Tompkins. This podcast is similar to the Pod F. Tompkast; however, Spontaneanation is fully improvised and in-the-moment, as opposed to the Tompkast, which was highly produced. Spontaneanation begins with an improvised monologue, accompanied on piano by Eban Schletter, much like the Pod F. Tompkast. The next segment is an interview with one of Tompkins's famous friends. The final segment is one long improvised story performed by Paul and guest improvisers, based on ideas discussed in the interview segment.

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. Tompkins played the character of a nightclub manager who is duped into reading Tenacious D’s ridiculous introductions during their open mic performances. He revived the role in the comedic band's film Tenacious D in The Pick of Destiny released in 2006.