Peter Parker develops super-spider powers after being bitten by a genetically altered spider. The game opens with an optional tutorial, narrated by Bruce Campbell, where Peter learns to use his powers and the player learns the controls of the game and how to read the HUD. After competing in a wrestling match as Spider-Man, Peter is cheated out of his prize money by the fight promoter. After the fight promoter is robbed by a thief, Peter lets the thief go out of spite. Later, Peter devastated when his Uncle Ben is killed by the leader of the Skulls gang. Peter uses his new powers to track down and defeat the murderer and learns it is the same thief he let go at the fight promoter’s office, the thief then dies by accidentally slipping out of a window while trying to avoid Spider-Man. Peter vows to use his powers for good and to fight evil in Manhattan. Meanwhile, Norman Osborn and OsCorp are investigating the appearance of this new hero. Anxious to develop his Human Performance Enhancer “Super Soldier” serum, the main goals of which are already exhibited by the super-hero, Osborn orders the capture of Spider-Man, deploying hunter-killer robots for this purpose. Spider-Man fights these robots and emerges victorious. Meanwhile, the Shocker (Michael Beattie) has just robbed a bank, and is driving away with his thugs as Spidey lands, only to be hit by Vulture. Spider-Man goes after Shocker first. His battle with Shocker leads him through Grand Central Station, into the sewers and to a subway station, where Spider-Man defeats him in a climactic battle. Afterward, Shocker tells Spider-Man about Vulture’s lair: an old clock tower on the Lower East Side of town. Spider-Man climbs Vulture’s tower (avoiding bombs), but Vulture escapes. He chases Vulture through the city. Spider-Man defeats Vulture around the Chrysler Building.
It is two years following the events of the first game. Spider-Man is trying to balance his civilian and superhero life, frequently late or absent for school, work, and leisure time with his friends. Following dinner with Mary Jane Watson, Peter thwarts an armed looting of an art museum, and tracks down an escaped robber, the Black Cat. Soon after this, he thwarts an attack in the streets of Manhattan by The Rhino. Meanwhile, Doctor Otto Octavius attempts to recreate nuclear fusion of that seen in the sun to provide an energy source for Manhattan. To control this fusion, he creates four metal arms which he can mentally control. His fusion creates a strong magnetic field, destroying the lab, killing his wife Rosie, and grafting his metal arms to his spine and giving his arms control over him. He blames Spider-Man for the incident, despite the fact that Spider-Man was not in the lab until the middle of it.
A new gang called the H-Bombers have blown up the Carlyle building, and Spider-Man comes in to save the day. He beats the bombers and saves a woman from being killed. The next day, Peter Parker narrates: “Just another day in the life of your friendly neighborhood Spider-Man! Lately, things have been going my way. I got the girl and New York finally likes me. Not that there are problems, but there is this new guy Eddie Brock at the Daily Bugle, and he is really starting to get on my nerves. Harry, my best friend, won’t talk to me. On top of that, new gangs have been dividing up the city, still its nothing I can handle. One weird thing, there hasn’t been any big super villain around since Doc Ock. I had this bad feeling that the sky is gonna fall or something and soon.”
The game has an open world/free-roaming concept. The combat system is reminiscent of the Rocksteady Studios-developed Batman game series using a freeflow design and counterattacks. Beenox took a cue from the Batman games, with Dee Brown, the head of Beenox, stating “I played both Batman games and liked them. For me, the Spider-Man character is very different than Batman. You have to approach both in a different way. I think the Rocksteady guys did a good job at providing what was required to make a great Batman game, and we’re doing everything we need to this time to make a great Spider-Man game.”
After Dennis Carradine, the man who murdered Peter Parker’s Uncle Ben, is murdered by a serial killer known as the “Carnage Killer,” Peter Parker also known as the vigilante Spider-Man decides to track down Carradine’s killer, and bring him to Ravencroft, a prison for the criminally insane. Oscorp CEO Harry Osborn and billionaire Wilson Fisk announce that their companies are working together to fund the Enhanced Crime Task Force, a privatized police force meant to contain criminals and Spider-Man, following an attack on Oscorp Tower by Herman Shultz (one of Carradine’s contractor whom Spider-Man encountered before Herman became Shocker). When Fisk offers to take Oscorp off of Harry’s hands, Harry rebuffs him. Fisk then decides to wait until Harry dies from the disease that killed Harry’s father, Norman Osborn.