The Amazing Spider-Man for Wii is a modified version of the main console version. It shares the story (Spider-Man has to rescue Manhattan from the Virus which made Curt Connors to Lizard), voice-overs and level set-pieces. However, there is one very important difference: the absence of all open-world elements. Peter Parker's apartment serves as hub from where the player chooses the next destination. This is usually the next level or a boss fight, but there are also challenge maps (either defeating a number of enemies within a given time frame or stealthily knocking out enemies) available. Solving missions rewards experience points which are used to improve Spider-Man's abilities.

Combat is similar to the main version and still takes many cues from Batman: Arkham Asylum: Spider-Man quickly switches between enemies and punches them; when the spider-sense is activated he can dodge and perform a counter-attack. A not disrupted flow builds up a counter which, when high enough, is used to perform a powerful attack. The web rush ability slows down time and allows Spider-Man to pick a destination to swing to. This can be used for surprise attacks or quick retreats.