This series marked Frank Welker's debut as the voice of Scooby-Doo, taking over from Don Messick (who died in 1997) and Scott Innes, while Welker also continued voicing Fred.

Casey Kasem returned to voice Shaggy after a five-year absence, and this would be the last Scooby-Doo series in which he voiced the character before retiring from the role in 2009 and later dying in 2014.

At Casey Kasem's request, Shaggy was made a vegetarian for this series.

Mindy Cohn took over the role of Velma from B. J. Ward, and Grey DeLisle returned as Daphne after previously voicing her in Scooby-Doo and the Cyber Chase and Night of the Living Doo.

The series was announced in January 2002 under the working title 'All New Scooby-Doo! The Animated Series' and was jointly picked up by Kids' WB and Cartoon Network, which had begun jointly selling advertising slots.

The recurring character Gibby Norton was modeled after his own voice actor, Eddie Deezen, while explorer Melbourne O'Reilly was based on Steve Irwin and Indiana Jones, and Mr. B appears to be based on actor John Turturro.

The Canadian band Simple Plan performed the show's theme song (written by Rich Dickerson) and appeared as themselves in the episode 'Simple Plan and the Invisible Madman,' which also featured their songs 'You Don't Mean Anything' and 'The Worst Day Ever'; another track, 'I'd Do Anything,' appeared in a chase scene in a different episode.

This was the first Scooby-Doo series produced in 16:9 widescreen, although it was cropped to 4:3 for broadcast; it also replaced the classic Hanna-Barbera sound effects with all-new original ones and rarely used the franchise's signature thunderclap sound.