In the year 2099, geneticist Miguel O'Hara worked on recreating the powers of the original Spider-Man for Alchemax, but refused to experiment on humans at such an early stage. Tyler Stone, Miguel's boss in Alchemax, spiked a drug on his drink to keep him loyal and allow the experimentation. To overcome the effect of the drug, Miguel spliced his own DNA and got spider-like powers. Miguel became the new Spider-Man to fight crime and Tyler Stone's corruption.
Soon into his career as a hero, he traveled back in time and befriended Peter Parker, teaming up with the original web-slinger to fight mutual enemies before returning to his original time.
Later on, time aberrations forced Miguel to once again travel back in time, but was confronted by the Superior Spider-Man. He sensed something was wrong, but reluctantly joined forces with Doc Ock. After the crisis was resolved, Miguel was stranded in the present, unable to return to 2099.
Once Peter Parker reclaimed his body, he and Miguel once again united to stop the Green Goblin from taking over New York.
Shortly afterward, Miguel met a woman named Tempest Monroe, who he fell in love with, and took a job at Parker Industries while fighting crime in the modern era and looking for a way to return to his version of 2099.
- In the 2011 video game, Spider-Man: Edge of Time, Spider-Man 2099 was voiced by Christopher Daniel Barnes who also voiced Spider-Man in the 1994 animated television series, Spider-Man: The Animated Series, Prince Eric in the 1989 animated musical fantasy film, The Little Mermaid, Spider-Man Noir in the 2010 video game, Spider-Man: Shattered Dimensions, and Electro in the 2012 animated television series, Ultimate Spider-Man.
- The character appears in the 2018 animated film Spider-Man: Into the Spider-Verse, voiced by Oscar Isaac. He appears in the film's post-credits scene, along with his A.I. Lyla, learning about the film's events while building a watch that allows him to travel to different dimensions while maintaining molecular stability. Once it is ready, he tests it by to traveling to Earth-67, though he immediately gets into an argument with that universe's Spider-Man. Isaac is set to reprise his role in the 2023 sequel, Spider-Man: Across the Spider-Verse.