He was interested in comics from an early age and dropped out of high school to pursue a career in the field. The only job he ever held outside of the comic field was working as an employee at Now and Then Books. "It was the first and only place in Kitchener that I ever felt truly comfortable before or since", Sim has said.
In the 1970s he published a fanzine called The Now and Then Times (financed by Harry Kremer, the owner of the comic book store after which the newsletter was named) and did work for such other fanzines as John Balge's Comic Art News and Reviews and Gene Day's Dark Fantasy and National Advisor. Sim often interviewed professional comics artists such as Barry Windsor-Smith, Harvey Kurtzman and Neal Adams.
Sim also created various other comics, including a newspaper comic strip called The Beavers which was published in the Kitchener-Waterloo Record, and wrote or drew stories published in anthologies such as Phantacea and Star*Reach. The Beavers also saw print in Star*Reach's sister funny animals comic Quack!.
Cerebus was published through Sim's company, Aardvark-Vanaheim which was run by his wife, Deni Loubert. The two met in 1976, married in 1979, and divorced after nearly five years.
In 1979, Sim was admitted to K-W Hospital by his wife and mother after several days of taking LSD. He later stated in his Getting Riel dialogue with Chester Brown that he was "diagnosed as a borderline schizophrenic." During his convalescence, Sim hit upon the idea of making Cerebus into a 300-issue series, something that had never been done in Western comics with the same artist and writer.
In the 1980s, when Cerebus was a large success for an independently produced comic book, Sim did much travelling to promote the series, which reached a peak circulation of 36,000 copies. In 1984 he began a collaboration with Gerhard, who handled the background drawings in the series. Aardvark-Vanaheim, managed by Loubert, began publishing other comics besides Cerebus, such as William Messner-Loebs' Journey and Bob Burden's Flaming Carrot. After Sim and Loubert's separation, Loubert started Renegade Press, which assumed publishing duties for all non-Cerebus Aardvark-Vanaheim titles.
Although Sim did not maintain a consistent monthly schedule for the entire run, which at times required an accelerated production schedule to catch up, he completed the Cerebus series on schedule in March 2004. He purchased Gerhard's stake in Aardvark-Vanaheim, and has made arrangements for the copyright of Cerebus to fall into the public domain following his death.
As of 2006, Sim is working on the Cerebus Archive Project, an online searchable database of Cerebus materials. Sim is also in the process of reading the Gospels and The Book of Revelation out of Brooke Foss Westcott and Fenton John Anthony Hort's 1881 interlinear Greek to English translation of The New Testament semi-weekly and taking notes. He has said that he plans to publish a commentary on it, using Chester Brown's artwork for the Gospel of Mark from Brown's unfinished gospel project as illustrations. Recently Sim said he may make his notes available as a free digital book. This project was discussed in Collected Letters: 2004, and in recent letters between Sim and his readers.
In late 2006 and early 2007, Sim conducted public readings of the 1611 King James Bible at the Registry Theatre in Kitchener in order to raise money for the Food Bank of Waterloo Region. His stated intention is to read the Old Testament, the New Testament, and the Qu'ran. All of these readings have been taped and are being sold on eBay to raise money for the food bank. This project was discussed in Collected Letters: 2004 and in recent letters between Dave and his readers.
Beginning in 2006, Sim began publishing an on-line comic book biography of Canadian actress Siu Ta titled Siu Ta, So Far.
In late 2007, Sim announced two upcoming projects. One, which he initially referred to only as "Secret Project One", is Judenhass ("Jew hatred"), a 56-page "personal reflection on The Holocaust" which was released on May 28, 2008. The other is a comic book series related to women's fashion, called glamourpuss, for which he did a "tour" of online forums related to comics in February 2008.
Sim's pioneering use of an extended, multi-layered storytelling canvas, divided in large arcs divided in mostly self-contained issues, was acknowledged by J. Michael Straczynski as his inspiration for the structure of Babylon 5.
Sim has criticized the use of copyrights to restrict the use of creations which would have more quickly become public domain under earlier copyright law. He has stated that other creators are free to use his characters in their own works, which he characterizes as an attempt to be consistent with his own appropriation of others' works.
The expression of these views caused major controversy in the comic book industry and among his readership, and were followed by a substantial decline in sales. In 1995, The Comics Journal #174 featured a Bill Willingham caricature of Sim on one of the covers, bearing the title Dave Sim: Misogynist Guru of Self-Publishers. Inside was a lengthy article written by Jonathan Hagey and Kim Thompson about responses to Sim’s piece. The article published responses from comics creators such as Alan Moore, Canadian Gregory Gallant (better known by his pen name Seth), Rick Veitch, Steve Bissette, and Sim’s friend (and fellow Canadian) Chester Brown. The responses ranged from anger to a belief that Sim was joking. The article also included a short interview with Sim's ex-wife, wherein she described the essay as evidence of Sim being "very scared". The article was accompanied by an illustration depicting Sim as a Nazi German concentration camp warden, standing in front of a gate with the name of his publishing company on the top. Piles of emaciated bodies lay within. In the essay in Cerebus #186, Sim characterized fellow self-publishing cartoonist Jeff Smith as an example of a man dominated by his wife. Smith contested this, and Sim later challenged Smith to a boxing duel to sort things out.
In 2001, Sim published another essay called "Tangent" in Cerebus #265, (April 2001). In it, Sim furthered the themes from Reads, describing the veering-off course (or tangent) he contends western society has taken due to the widespread acceptance and proliferation of feminism, beginning in 1970. The Comics Journal posted the full essay on its website, although a short introduction by staff distanced the Journal from the ideas therein, calling them "nutty and loathsome". The site's message board received many responses, mostly opposing Sim's arguments. The next issue of the journal included a rebuttal to the first Tangent by "Ruthie Penmark", a pseudonym for Anne Elizabeth Moore, one of the Journal's editors. Several years later, in TCJ issue #263, the Journal devoted a section to discussion of Cerebus. In it was a reprint of a 'zine essay by Renee Stephen, written in 2001 about the Tangents, titled Masculinity's Last Hope, or Creepily Paranoid Misogynist? : An Open Letter to Dave Sim.
Recently, as a response to the criticism he has received, Sim has declared that he will only correspond with people who first agree that he is not a misogynist. , saying he will only answer letters and submissions sent under the header, "I don't believe Dave Sim is a misogynist."
Early in the 1990s, Groth took issue with Sim’s stance of self-publishing as the best option for creators, and began to disseminate the view that it was best to work for a publisher, mentioning Ivan Boesky's address to the University of California's commencement ceremony in May 1986 where Boesky informed his audience that "greed is all right, by the way. I want you to know that. I think greed is healthy. You can be greedy and still feel good about yourself." Sim took this as Groth implying that the motivation for self-publishing is greed, whereas his belief was that self-publishing was the best option for reasons of principle: creative autonomy and ownership of one's own creations.
In 2000, Groth and Thompson published "The Comics Journal's 100 Greatest Comics of All Time", a list selected by its writers, which some commentators noted appeared biased towards Fantagraphics titles and seemed to pointedly omit Cerebus.
Later, on a panel at the San Diego Comic Con Groth indicted Sim in a "Nuremberg-style tribunal designed to bring to light the most deserving criminals who had over the past decade and longer besmirched the good name of the comics art and industry Sim was charged with boosting the speculation boom in the comics market in 1992, early boosterism of Image Comics, making a "misogynist rant", and promoting self-publishers at their expense, this last wherein Groth accused Sim of promoting self-publishing to the point of possibly bankrupting thousands of self-publishers.
Sim was interviewed by Tom Spurgeon for the magazine in 1996, the second part of which interview was published eight issues after the first, which was interpreted by Sim as a slight. Despite this adversarial relationship over the years, Groth telephoned Sim to congratulate him upon the completion of his work on Cerebus in December 2003, and later published an issue of the Journal featuring a critical roundtable on Cerebus.
Collected Letters: 2004 (ISBN 0-919359-23-X) collects Sim's responses to readers' letters (the original letters are not included) after the publication of Cerebus #300.