Orphaned at the age of six, Peter Parker is an outcast and withdrawn teenaged science prodigy, who lives in Queens, New York.

While attending a field trip to a scientific corporation, he is bitten by a genetically-modified spider and as a result, begins to develop spider-like superpowers, including enhanced strength, speed, agility, stamina, durability and reflexes, along with the ability to crawl solid surfaces and a sixth sense, which warns him of imminent danger, all of which he decides to utilize for personal gain.

It relaunched as Ultimate Comics: Spider-Man and features Miles Morales and a new artist named Sara Pichelli.

[4] The Ultimate Spider-Man branding would later be re-used in 2024 for a new unrelated comic book series set on Earth-6160, written by Jonathan Hickman and drawn by Marco Checchetto.

[10] As the series progressed within the next two years, reception and sales stayed strong, helped by the fact that Bendis and Bagley quickly found chemistry and enjoyed working together.

Despite the book's apparent cancellation, in August 2009 Ultimate Spider-Man was relaunched with Brian Michael Bendis returning as writer and David Lafuente as artist.

[11] The book finished its run with #160 and subsequently was relaunched as Ultimate Comics: Spider-Man with art by Sara Pichelli.

For issues 200 and 234 up, Marvel Legacy considers #54–133 and #150–160 to be wrongly numbered, and accounts for all major Ultimate Spider-Man comics written by Bendis:[13]