Prior to the beginning of Spider-Gwen, high school student Gwen Stacy was bitten by a radioactive spider. This granted her all of the quintessential Spider-Man powers, and Stacy began her career as Spider-Woman. In her regular life, she began a relationship with Peter Parker and formed a friend group with Parker and ostracized new student Harry Osborn, who is later revealed to have had a crush on her. Meanwhile, Peter began his infatuation with Spider-Woman — without knowing that she is secretly his best friend Gwen Stacy. The bullying Peter suffered worsens, and eventually he creates a formula that turns him into a lizard mutant.

On prom night, after he is being bullied yet again, he injects himself with the formula and transforms, going crazy. Gwen Stacy then dons her Spider-Woman costume and fights Peter, defeating him, but she accidentally pushes him too hard and kills him. Peter regresses to his human form in Gwen's arms, telling her he just wanted to "be special" like her and prompting her to realize what she has done. She then runs from the scene, creating the public misconception that Spider-Woman has murdered Peter Parker and is a menace to society and setting up the scene for the Spider-Gwen series.