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. Madureira produced a total of nine issues in four years. 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.
In July 2007, Darksiders was announced, of which Joe Madureira is creative director.