Seth's cartoons in a style influenced by the classic cartoonists of The New Yorker. His work is highly nostalgic, especially for the early-to-mid-20th Century period, and of Southern Ontario. His work also shows a great depth and breadth of knowledge of the history of comics and cartooning.
Clyde Fans, the story of two brothers whose trade in electric fans 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.
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