Spider-Man: Edge of Time is a follow-up to Shattered Dimensions, and similarly it has more than one Spider-Man takes a starring role. Here, it is the regular, classic "Amazing" Spider-Man, and Spider-Man 2099 – in a story awash in time travel, temporal battles, and Anti-Venom. The backbone of this story seems to play out more like a Spider-Man 2099 story, since he is the only character truly aware of the happenings in the game, and the changes that both Spider-Men encounter. From the opening, things are bleak for Amazing Spider-Man who begins the game nearly dead, and 2099 is the only one who can help. A new villain Walker Sloan enters the picture with a plan to rebuild the past (from the year 2099) in his image and design, which turns to affect both Spider-Men. From this point, chaos unfolds in typical comic-book fashion with gameplay evenly split between Amazing Spider-Man and Spider-Man 2099, with every other level interwoven with the events of one Spidey to the other.

In the year 2099, Miguel O'Hara, the Spider-Man of his era, investigates Alchemax scientist Walker Sloan and uncovers a dangerous plot: Sloan intends to travel back in time to found the powerful corporation decades before its true origin, rebuilding history in his own image. O'Hara fails to stop Sloan from stepping through his time gateway and is briefly trapped between dimensions, where he witnesses a chilling vision of his predecessor, Peter Parker, being killed by an unknown assailant. Returning to a drastically altered version of 2099, O'Hara uses archived DNA to forge a mental link across time with Parker, working in the past, to warn him of his impending death. As the two Spider-Men are drawn together, they discover that every action in one era now ripples directly into the other.