Madureira's first published work was an eight-page story for the anthology series Marvel Comics Presents, starring Northstar. He became the regular penciler on Uncanny X-Men in 1994 illustrating that book's installments of the Age of Apocalypse storyline.
He left Uncanny X-Men in 1997 to work on his own sword and sorcery series Battle Chasers for Wildstorm Comics' creator-owned Cliffhanger imprint (before it was sold to DC Comics).
Madureira produced a total of nine issues in four years (publishing two to three a year), a pace for which he was criticized. He canceled Battle Chasers #10, and placed the series "on hold" after forming a game development company called Tri-Lunar with Tim Donley and Greg Peterson.
With Tri-Lunar, he created concept art on a game called Dragonkind which was canceled when Tri-Lunar went out of business. He then went to work for Realm Interactive, another start-up company, on Trade Wars: Dark Millennium. When Realm Interactive was acquired by NCsoft, he continued to contribute to the game as it evolved into Exarch, and was eventually released as Dungeon Runners.
Madureira returned to the comic book industry as the artist on Marvel's The Ultimates 3, with writer Jeph Loeb. The second issue was published in January 2008, the third issue released on February 20, 2008. Ultimates 3 #4 came out on June 25, 2008.
In July 2007, Vigil Games' Darksiders was announced, of which Joe Madureira was creative director. It follows War, one of the Four Horsemen of the Apocalypse, on his quest to find out who prematurely triggered the apocalypse. It was released on Xbox 360 and PS3 in early 2010.