Seth's first published comics work was as an illustrator on the Vortex Comics series Mister X, but he soon moved to his own series, Palooka-ville (published by Drawn and Quarterly), which was part of a miniature boom in non-genre alternative comics from Canada in the 1990s. Seth, Chester Brown, and Joe Matt not only also began their own semi-autobiographical series at the same time but were friends and sometimes depicted each other in their stories. Palooka-Ville began as a low-key chronicle of the artist's daily life but moved on to longer and more ambitious stories, including what was later collected as the graphic novel It's a Good Life, If You Don't Weaken— an apparently autobiographical tale that was actually fiction.

He is also a magazine illustrator and book designer, perhaps best known for his work designing the complete collection of Charles M. Schulz's classic comic strip Peanuts. The books, released by Fantagraphics Books in 25 separate volumes (so far) combine Seth's signature aesthetic with Schulz's minimalistic comic creation. Similarly, he is designing the Collected Doug Wright, and the John Stanley Library.

He provided the artwork of Aimee Mann's 2001 album Lost in Space.

Clyde Fans, the story of two brothers whose trade in electric fan suffers and eventually goes out of business from the failure to adapt to the rise of air conditioning, was serialized in Palooka-ville. Seth's short graphic novel Wimbledon Green, about an eccentric comic-book collector, was published in November 2005.

In April 2006, Penguin Classics released the revised Portable Dorothy Parker, with a jacket and French flaps designed and illustrated by Seth. He said, "It’s fun when you care about the project, definitely. In fact, I’ve been a commercial illustrator for years, besides being a cartoonist, and that's not fun. That's like the kind of thing, I find, you're just selling style in a way."

From September 2006 to March 25, 2007, Seth serialized a graphic novel titled George Sprott (1894—1975), for the Funny Pages section of the New York Times Magazine. Selections from George Sprott were featured in Best American Comics 2009. In the liner notes of that publication, Seth announced he was expanding Sprott into a book, filling in gaps that were cut to meet the restraints given by NYTM. The book was published by Drawn & Quarterly in May 2009.

Seth's affection for early- and mid-20th century popular culture and his relative disdain for pop culture since then is a recurrent theme in his work, both in terms of the characters (who are often nostalgic for the period) and his artistic style. (Although, as a teenager, he was a vocal fan of mainstream superhero comics; he even had a couple of fan letters published.)

Seth's artwork has landed on the cover of The New Yorker three times, which he said was a professional milestone he was happy to achieve.

A selection of Seth's original models (studies for his fictional city, Dominion) was included in an exhibition at the Phoenix Art Museum in Phoenix, AZ from April 21 through August 19, 2007.

In a collaboration between the Kitchener-Waterloo Art Gallery, Seth, and RENDER, one of the buildings from Seth’s Dominion City project has been re-built as a walk-in theatre in KW|AG’s Eastman Gallery.

Eisner Award

• Best Publication Design (The Complete Peanuts), 2005

Harvey Award

• Special Award for Excellence in Production/Presentation (The Complete Peanuts), 2005

Ignatz Award

• Outstanding Artist, 1997
• Outstanding Graphic Novel or Collection (It's a Good Life If You Don't Weaken), 1997

Graphic Novels

• ( ) "Bannock, Beans & Black Tea" - Montreal: Drawn and Quarterly, ISBN 1-896597-78-5
• (1996) It's a Good Life, If You Don't Weaken — Montreal: Drawn and Quarterly, ISBN 1-896597-70-X
• (2000) "Clyde Fans: Part One" - Montreal: Drawn and Quarterly, ISBN 978-1-894937-09-2
• (2003) "Clyde Fans: Part Two" - Montreal: Drawn and Quarterly,
• (2004) Clyde Fans: Book One — Montreal: Drawn and Quarterly, ISBN 1-896597-84-X
• (2005) Wimbledon Green — Montreal: Drawn and Quarterly, ISBN 1-896597-93-9
• (2009) "George Sprott" - Montreal: Drawn and Quarterly, ISBN 978-1-897299-51-7

Other

• (2001) Vernacular Drawings [sketchbook] — Montreal: Drawn and Quarterly, ISBN 1-896597-41-6
• (2002) Inner Drawings and Cover Art for the Record Lost In Space by Aimee Mann, Super Ego Records.
• (2005) Design and Inner drawings for "Christmas Days", by Derek McCormack, Anansi, 2005, ISBN 978-0887841934.
• (2006) Forty Books of Interest: A Supplement to Comic Art No. 8
• (2007) Design and Inner drawings for "Cocktail Culture", by Mark Kingwell, 2007, ISBN 978-1846271144
• (2008) Design and Inner drawings for "The Idler's Glossary," by Joshua Glenn and Mark Kingwell, Biblioasis, 2008, ISBN 978-1-897231-46-3.
• (2009) Cover of the Criterion Collection's DVD release of Leo McCarey's Make Way for Tomorrow (spine #505).