The cartoon version basically picked up where the popular 1966 movie left off. A team of government scientists known as the "Combined Miniature Defense Force" had been voluntarily shrunk to microscopic size in order to gain access to areas too small for normal-sized explorers. Commander Jonathan Kidd led the crew, which traveled aboard a high-tech vehicle called the Voyager. With scientist Busby Birdwell (who built the ship) at the controls, the Voyager could dive underwater like a sub, fly through the air like a plane, or rocket off into space like a UFO.

The cartoon version also featured Professor Carter, biologist Erica Lane, and the mystical Guru, who possessed some kind of "mysterious power." Whatever it was, it came in handy—in every episode, the crew faced unknown microscopic creatures, as well as shrunken enemy spies, all out to stop the CMDF.

While the animation was simple and the story lines even simpler, Fantastic Voyage won points for its ability to stay true to the original movie. Each episode paid close attention to the detail of the miniature world, which was, without a doubt, the main hook of the show. The producers also refused to patronize their audience with simplistic dialogue, giving the show a more grown-up feeling.