When a failed nuclear fusion experiment results in an explosion that kills his wife, Dr. Otto Octavius (Alfred Molina) is transformed into Dr. Octopus, a cyborg with deadly metal tentacles. Doc Ock blames Spider-Man (Tobey Maguire) for the accident and seeks revenge. Meanwhile, Spidey's alter ego, Peter Parker, faces fading powers and self-doubt. Complicating matters are his best friend's (James Franco) hatred for Spider-Man and his true love's (Kirsten Dunst) sudden engagement to another man.
Peter Parker is beset with troubles in his personal life as he battles a scientist.