The story is split between the narratives of Peter Parker, and Mary Jane Watson, as they each reflect on their lives. Richard Parker, and his wife, Mary, leave their infant son, Peter, with Parker's brother, Ben, and his wife, May. Philip Watson drunkenly screams at his wife, Madeline, in front of their two daughters, Gayle, and Mary Jane. This early trauma influences Mary Jane's development. Years later, Mary Jane catches her first sight of Peter. To mask the trauma of her parent's divorce, Mary Jane fabricates a happy-go-lucky persona. At the Midtown High Science Hall, Peter is bitten by a radioactive spider.
The spider bite gives Peter super-human powers. Peter uses those powers to become a celebrity. At this point, Mary Jane is the most popular girl in high school. A visit from her sister, Gayle, and her new husband, Timothy Byrnes, unnerves Mary Jane. Gayle is pregnant, and Byrnes is clearly not happy about it. After a television appearance, Peter, now calling himself "Spider-Man", stands idle as a robber runs past him. Peter's Uncle, Ben, takes notes of Peter's change in demeanor, unaware that Peter's brighter mood is a result of his secret life as Spider-Man. Mary Jane becomes the very definition of a party girl. Peter achieves massive fame as Spider-Man.
The robber Spider-Man allowed to escape murders Uncle Ben. Mary Jane witnesses Spider-Man exiting from Peter's bedroom window. Spider-Man brings the robber to justice. Upon realizing that the robber is the same man he allowed to go free, Spider-Man holds himself accountable for Ben's death. Spider-Man learns that with great power comes great responsibility. Mary Jane throws herself into a hedonistic lifestyle. Doctor Otto Octavius is injured in a radioactive explosion. The armature that Octavius used in his research is fused to his body. Spider-Man becomes a costumed crime fighter, taking down the likes of Kraven The Hunter.
May, and Mary Jane's Aunt, Anna, conspire to set Peter up on a date with Mary Jane. Neither Peter, nor Mary Jane, are thrilled with the idea. Peter is much more interested in Betty Brant, a secretary at the Daily Bugle. Mary Jane fears Peter may be too much like her abusive father, as Peter also keeps secrets. Mary Jane tanks the blind date by feigning illness. Two years pass. Spider-Man continues to fight super villains, like the Molten Man. Peter dates Liz Allen, and graduates from High School. May collapses, due to a radioactive particle in her blood, garnered by an earlier blood transfusion from Peter. As Spider-Man, Peter consults with Doctor Curt Connors, for a solution.
Connors points Spider-Man to Iso-36. Before Spider-Man can get his hands on it, the Iso-36 is stolen by the Master Planner. Spider-Man tracks the Master Planner to a hidden underwater base. The Master Planner is revealed to be Doctor Octopus. After a pitched battle, Spider-Man defeats his foe, and provides the Iso-36 to May's doctor's May makes a full recovery. Byrnes leaves Gayle, pregnant with their second child. Madeline dies before she can witness the birth of her second grandchild. Mary Jane refuses to compromise her life for her sister. Spider-Man continues to battle the likes of Kraven The Hunter, The Molten Man, The Looter, and The Green Goblin.
Mary Jane moves in with her Aunt, Anna. Mary Jane gets a job, as a waitress, and a dancer. Mary Jane moves out on her own. Mary Jane continues to be both drawn to, and repelled by, Peter. Mary Jane finally consents to meeting Peter. Octavius moves in with May. His short time of happiness is disrupted by Peter, resulting in a battle with Spider-Man. Doctor Octopus steals radioactive waste. Peter marries Mary Jane. Doctor Octopus surreptitiously observes the wedding ceremony. Doctor Octopus sends a drone to attack Peter, Mary Jane, and May. The drone issues a challenge to Spider-Man. Peter, as Spider-Man, confronts Doctor Octopus, in the Master Planner's old underwater base.
Doctor Octopus intends to detonate the radioactive waste under Manhattan, leveling half the city. Spider-Man battles Doctor Octopus. Spider-Man tricks Doctor Octopus into flooding the base. Their battle carries them out into the East River. After a desperate struggle, Spider-Man manages to make it to the surface, with Doctor Octopus in hot pursuit. At the mercy of Doctor Octopus, Spider-Man is saved when the radioactive waste detonates prematurely, seemingly killing Doctor Octopus. Shaken by the attack, Spider-Man, as Peter, reconsiders his marriage to Mary Jane. Fortunately for Peter, Mary Jane sets him straight.