While covering the launch of John Jameson's one-man mission to Counter-Earth (another Earth located on the far side of the Sun), Spider-Man attempts to stop his two symbiote adversaries Venom and Carnage from boarding the shuttlecraft. Blamed for losing contact with Jameson by J. Jonah Jameson of the Daily Bugle, Spider-Man becomes a target of persecution by the media and the public at large, with a bounty placed on his head. After John Jameson had made contact with Earth through a distress signal, Spider-Man borrows nanotechnology from Reed Richards to design a new suit that incorporates built in webshooters, stealth technology and anti-symbiote sonic weaponry. Making his way to Counter-Earth after persuading an attacking Nick Fury to let him rescue Jameson, Spider-Man learns that Jameson has fallen in with a band of freedom fighters opposed to the High Evolutionary whose Beastials, hybrids of animal and humanoid attributes, are the dominant species whilst humans are the second-class minority.

With Jameson reluctant to return until all of the Beastials are defeated, Spider-Man elects to remain on Counter-Earth, blending in as best as he can as Peter Parker, taking up residence in the apartment of a doctor, Naoko Yamada-Jones and her son Shane and fighting the High Evolutionary, his Knights of Wundagore, and his Machine Men alongside the rebels as Spider-Man. It is soon discovered that Venom and Carnage are also on Counter-Earth, and are following orders from the Synoptic, a hive-minded legion of Counter-Earth symbiotes.

This series also shows the animated version of John Jameson's Man-Wolf form, superhero versions of mainstream villains Green Goblin and Vulture, and Counter-Earth's counterparts of Kraven the Hunter and Electro.