The show's original working title was 'Children of the Atom', a reference to the X-Men comics, but this was scrapped because the network did not want the title to reference children.

The series bible was written by Robert N. Skir and Marty Isenberg (the latter uncredited), who aimed to return the X-Men to their comic book roots as 'The Strangest Teens of All' by depicting them as high school students learning to control their powers.

Early concept art showed the X-Men in classic gold-and-black comic costumes, with Spyke sporting cornrows, Rogue's outfit exposing her midriff, and Jean Grey wearing a female version of Cyclops' costume; Storm was originally drawn in white rather than black.

Mystique was originally intended to be depicted nude, akin to her later film counterpart, but Warner Bros. rejected this for a Kids' WB production; a brief clothed scene resembling her film design still appears in the Season 1 finale.

The Rogue/Kitty dance scene in the episode 'Spykecam' was modeled after a similar dance scene in the Buffy the Vampire Slayer episode 'Bad Girls', and the writers have admitted being fans of Buffy.

Buffy the Vampire Slayer creator Joss Whedon has openly credited Kitty Pryde as an inspiration for the character of Buffy Summers.

In the first season, one of Wolverine's Danger Room training programs is named 'Logan's Run X13', a reference to the novel/film Logan's Run.

The show was produced in the United States, with voice recording done in Canada, while animation was outsourced to Madhouse and Mook Animation in Japan and DR Movie and White Line in South Korea; it was the first X-Men animated series to use digital ink and paint.

The show's monthly budget was $350,000, and it ended after four seasons likely due to Warner Bros. wanting changes as well as business strategy shifts involving Nickelodeon in 2003, according to co-producer Robert N. Skir.

A tie-in X-Men: Evolution comic book by Devin K. Grayson launched in January 2002 but was abruptly canceled after nine issues due to low sales, leaving an unresolved storyline meant to introduce the show's version of Mister Sinister.