After defeating the Green Goblin the life of Peter Parker (Tobey Maguire) changes completely. Fearing that Mary Jane (Kirsten Dunst) suffers some risk because he is Spider-Man, Peter keeps hiding her love and stays away from her. At the same time must deal with Harry (James Franco), his best friend, whose anger at Spider-Man becomes ever greater, considering it to be the murderer of his father. Also his Aunt May (Rosemary Harris) is going through a difficult time after the death of his Uncle Ben, also wondering at the behavior of his nephew. While to deal with their particular problems Peter still gets bad news: the emergence of Dr. Octopus (Alfred Molina), a man who has tentacles attached to the body.