While the game directly adapts the plot of the film, it builds upon it by including additional characters and elements from the Spider-Man comic books and other aspects of the Marvel Universe.

Most actors reprise their roles from the film, including Tobey Maguire, James Franco (the first time he does so as Josh Keaton provided Harry's voice in the previous two games), Topher Grace, Thomas Haden Church, and J. K. Simmons.

Missions are structured in a non-linear manner like in the Grand Theft Auto series, meaning that the game features multiple storylines which can be played in any order the player desires.

It also features the symbiote black suit, which is automatically unlocked after a number of story missions and introduces a "rage" mechanic, that is charged up by attacking enemies and allows the player to deal extra damage.

The New Goblin is also briefly playable in the final mission of the game across all three platforms, and is available as downloadable content for both PlayStation Network and Xbox Live.

Peter Parker in his civilian outfit is also playable on PC through mods, and through a glitch that prevents progression in certain story missions across all three platforms.

The main narrative is mostly unchanged, except for several slightly altered missions, while most of the secondary storylines focusing on characters not featured in the film have been removed and replaced with new ones.

During the main storyline, the black suit requires to be removed regularly, because if worn for too long, the symbiote will corrupt Spider-Man, leading to a game over.

After completing the main storyline, the black suit's rage meter will instead deplete to zero percent without killing Spider-Man, once it reaches its limit.

Unlike previous Spider-Man games, these random missions are activated through a radio transmission, allowing the player to accept or decline them, and may vary from stopping muggings to delivering fruit pies.

By flicking the Wii Remote & Nunchuck, the player can perform various actions such as combat, and one of Spider-Man's trademark abilities, web swinging.

Peter's former best friend, Harry Osborn, who also learned his secret, despises him because he falsely believes that Spider-Man murdered his father, while his job at the Daily Bugle is threatened by a new rival, Eddie Brock.

The following day, Spider-Man continues to fight crime in Manhattan, and battles each of the four warring gangs, making quick work of the Apocalypse, whose leader is defeated and arrested.

Meanwhile, corrupt science corporation MechaBioCon dispatches their top assassin, Mac Gargan, to break Rhino out of prison, catching Spider-Man's attention.

While investigating MechaBioCon, Spider-Man discovers that Gargan turned to them to remove his mechanical scorpion tail so that he could lead a normal life, but they instead experimented on him and placed him under mind control.

With the help of a friendly scientist, Dr. Jessica Andrews, who disapproves of the company's experiments on Gargan, Spider-Man finds and frees him from the mind control.

Returning home, Peter is enveloped by the symbiote, creating a black Spider-Man suit that enhances his powers and increases his aggressiveness.

The following day, Peter discovers that Eddie Brock hired an impostor Spider-Man to pretend to be committing a robbery so that he could photograph him and earn a promotion.

This, combined with his aggressiveness towards Mary Jane during a date, makes Peter realize that the symbiote is negatively influencing his behavior, and he attempts to remove it at a nearby church.

Harry rescues Mary Jane and defeats Marko before Venom kills him by knocking him off his glider and sending him falling to his death.

The game ends with Peter resuming his never-ending battle against crime, while stating that the only way to honor and remember those he loves is by never giving up being Spider-Man.

The next day, Spider-Man investigates several humanoid lizards seen in Central Park, and continues his battle against the H-Bombers, stopping them from blowing up the Daily Bugle's Printing Plant and Regional Office.

Elsewhere, an escaped convict named Flint Marko becomes the Sandman after accidentally falling into an experimental particle accelerator that fuses his body with the surrounding sand.

He then fights and defeats the Bombers' leader, who is revealed to be businessman Luke Carlyle, who turned to crime after a story published by Jameson ruined his company.

Unfortunately, Marko is too strong to be defeated, forcing Spider-Man to don the symbiote suit, then ultimately succumbed to its violent intent and unable to remove it.

Later that night, the symbiote suit’s influence on Peter made Mary Jane fears it during their date and while he fights crime against a group of robbers in front of her.

Later, Spider-Man encounters the Sandman, but is unable to defeat him, so he returns home, where the alien symbiote spots him, creating a new black suit that enhances his powers.

[16] For the Nintendo DS version, GameSpot praised the number of moves, Tobey Maguire's voice acting, and the variety of missions, but criticized the soundtrack.

[76] In December 2019, gameplay footage of the Wii version of Spider-Man 4, developed by Eurocom, was posted on YouTube, showing the prototype of the game.

[77][78] In September 2021, gameplay footage of the cancelled Xbox 360 version was revealed to the public, showing Spider-Man web-swinging through Manhattan and fighting an enemy gunship and several thugs.