The series was initially ordered by MTV in January 2002 to be an adaptation of the Ultimate Spider-Man comics by Brian Michael Bendis, but after the success of Sam Raimi's 2002 Spider-Man film, it was reworked to follow that film's continuity as a sequel.

Because Spider-Man 2 (2004) contradicted the events of this series, it ended up existing in its own separate continuity rather than truly continuing the film series.

Michael Rosenbaum was approached for the lead role of Peter Parker but did not audition, and the part eventually went to Neil Patrick Harris.

Neil Patrick Harris, Lisa Loeb, and Ian Ziering were announced as the primary voice cast in May 2002.

Peter Parker was originally meant to wear baggier clothes to hide his superhero physique, but cost-effective limitations of the cel-shaded CGI made it hard to render clothing folds, so his everyday outfits were redesigned to be close-fitting and contemporary instead.

The character of Aunt May was left out of the series (appearing only as a photograph in Peter's bedroom) because MTV executives worried that featuring elderly characters would turn off their target youth audience.

The show was canceled after just 13 episodes reportedly due to low ratings; director Brandon Vietti said that if it had continued, he planned to introduce Mysterio and Vulture and use more of Kraven the Hunter.

In 2004 the series received an Annie Award nomination for Outstanding Achievement in an Animated Television Production, and the episode 'Keeping Secrets' was nominated for Outstanding Storyboarding in an Animated Television Production.