His comics are drawn in a round icon-like cartoony style, although their content is often realistic or autobiographical. He has published 3 graphic novels, as well as several short pieces for the Swedish comic anthology Galago.
He is possibly most famous for his comic about Per-Olof Svensson, the formerly accused, subsequently acquitted murderer of then Swedish Minister for Foreign Affairs Anna Lindh. By a weird twist of fate, shortly in connection to the murder allegations, a short comic in Galago was published. According to Gärdenfors, he had met Svensson during a stay in Lund, and included him in his comic as a subject of mythomania. In 2005, Gärdenfors has had his book Lura mig (Fool Me) published, containing interviews with different people he considers mythomaniacs, and his comments about the media coverage of the event.
Alongside his childhood friend Calle Thörn, he is also a member of the underground hip-hop duo "Las Palmas" that received a lot of airtime on Swedish radio in the fall of 2004, primarily with the song "Spökskrivare" ("Ghostwriter"), claiming that it actually was Simon who had written all famous hip-hop songs. He is also part of an additional hip-hop project, Far & Son (Father and Son), featuring Frej Larsson of Slagsmålsklubben.
His graphic novel The 120 Days of Simon (Simons 120 dagar) was published in English translation by Top Shelf Productions in 2010.
In 2008, Gärdenfors hosted a six-episode series on ZTV titled The Simon Gärdenfors skräpkultur-show (The Simon Gärdenfors Junk Culture Show), with each episode focusing on a different category of "junk culture" such as candy wrappers, comics, and pinball.
His father Peter Gärdenfors is a philosopher and professor of Cognitive Science at Lund University, Sweden.