Soon after this, he thwarts an attack in the streets of Manhattan by The Rhino. Following dinner with Mary Jane Watson, Peter thwarts an armed looting of an art museum, and tracks down an escaped robber, the Black Cat. Spider-Man is trying to balance his civilian and superhero life, frequently late or absent for school, work, and leisure time with his friends. It takes place two years following the events of the first game. The player can do random tasks to earn 'hero points,' which must be accumulated to continue with the story. The player can explore Manhattan, Roosevelt Island, Ellis Island, Liberty Island, and a mysterious label on the map over the water claiming ' Governors Island' (which was omitted from the final version of the game due to time constraints) with many sidequests for the player to complete. The player has the ability to choose either to go on with the storyline or swing around the city. At the end of the game, it becomes possible to unlock a warehouse in which the player can again fight thugs and villains such as Shocker, Rhino, Mysterio, Doctor Octopus, and an additional boss, Calypso, who is not found elsewhere in the game.

While street thugs only have handguns, machine guns, crowbars and their fists to protect them, the super-villains and their minions have their various unique powers and weapons that they use to either steal, cause terror or defeat Spider-Man.

The PSP version of Spider-Man 2 was compared to playing the original Spider-Man movie game. The home console versions were also innovative in that physics-based algorithms simulated Spider-Man's web swinging in three dimensions, creating a new game mechanic unlike the traditional jumping or flying of previous Spider-Man games. The Treyarch version of the game allow the player to freely roam around Manhattan, Roosevelt, Ellis, and Liberty Islands.

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