The PSP received its own adaptation of the superhero sequel Spider-Man 2. Unlike the console version with its open-world design, the PSP game is strictly linear. Spider-Man must make his way through 19 levels, each presenting him with a series of challenges. He must beat up thugs and robots, save a police car from dropping from a bridge, turn on the sprinkler system in a burning warehouse, carry away civilians from a failed fusion experiment, rescue hostages in a museum and much more. Spidey can swing from buildings, pull himself up to the ceiling and crawl on walls to get around. To defeat the many enemies, he can use a variety of kicks and punches which can be built up into combos. His webbing comes into play in various ways: he can shoot it at enemies to knock them out temporarily and must also use it to complete various objectives, like fixing leaky pipes for the sprinkling system. During the game, Spidey earns Hero Points, which can be spent after each level to unlock new moves and some bonuses. Hero Points are awarded for completing a level, using combos, high levels of health and webbing remaining, time used and secret spider symbols found.

The game follows the story of the film only loosely (in the levels concerning Doctor Octopus). Many other Spider-Man villains are featured and must be defeated, including Mysterio, the Rhino, the Shocker and the Vulture. The story is told through a mixture of pre-rendered and in-game cutscenes, for which film actors Tobey Maguire, Kirsten Dunst, Alfred Molina and JK Simmons reprise their roles.