The Amazing Spider-Man is a tie-in to the movie of the same name. The story is a direct continuation of the movie and deals with an experiment gone wrong: Oscorp researches a cross-species mutation virus; the same which caused Lizard to appear. This virus reaches Manhattan and Spider-Man has to help the infected humans and find a cure.

This version returns to the open world-concept which was abandoned in the previous few installments. Spider-Man swings through Manhattan, although the web-shooting is performed automatically by pressing a button, on the way to the next plot point. Those are linear levels in which Spider-Man visits locations like sewers or laboratories and spends most of his time fighting enemies, including the new robot foes. The combat system is reminiscent to the free-flow system used in the Batman: Arkham series: Spidey quickly moves between enemies and bashes them; when his spider-sense goes off the player needs to use the evade button before getting hit. Because of Spider-Man's special abilities, he can walk on the ceiling and evade some combat sequences or use his web for a stealth takedown. It is also possible to quickly retreat to the ceiling in case the hero is on the losing side of battle. Besides combat, the levels feature maneuvering, a few open-the-door puzzles and boss fights.

Of course there are various distractions in the open world sequences, the most important being side missions. In those Spidey has to solve smaller tasks like exploring Oscorp labs, passing acrobatic challenges, photographing stuff or bringing infected people to a clinic. All this rewards experience points which can be used to improve Spider-Man's abilities. The collectibles in this game are comic book pages which unlock iconic Spider-Man issues. When in the open world, the player can activate Spidey's web rush ability by choosing on of the designated points on the map: then the game takes control and automatically swings to the point.