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, slated to be released by Fantagraphics Books in 25 separate volumes combine Seth's signature aesthetic with Schulz's minimalistic comic creation. He provided the artwork for Aimee Mann's 2001 album Lost in Space.
Clyde Fans, the story of two brothers whose trade in electric fans suffers and eventually went out of business from the failure to adapt to the rise of air conditioning, has been 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."
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 twice, 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 21st through August 19th 2007.