The Yellow Zone serves as a shelter for survivors is present here, but a close infected threat demands intense martial law be in place.

In the Green Zone, Blackwatch and the US Marine Corps have set up a safe zone here for survivors where normal life continues despite the disaster. The whole city is now split into three zones and each zone consists of different districts. The infected enemies have evolved since the first game, resulting in new enemies such as the Goliath and Spiked Brawlers. Mutations can also be gained by completing Blacknet sets, which are missions unlocked by hacking into Blacknet, the communications network of Blackwatch. By entering and destroying the infected inside a lair, mutations can be gained which can be used to upgrade Heller. The Hives from Prototype have been upgraded and are now known as Infected lairs, which are located around the city. Collecting the full set for a region will reward players with a mutation. A new type of Collectables called Blackbox. Consuming a WoI target starts a new mission, related to Blackwatch or Gentek.

The side quests and the Web of Intrigue have been integrated into the main storyline. The power selection wheel has also been upgraded, players will now be able to assign two powers for quick access and switch between them in a heated battle. The arsenal has been upgraded with a variety of new weapons, which Heller will be able to use by stripping them from the vehicles they are attached to. The Sonar ability allows players to find hunt targets by sending out a 'pulse' which will then come back with the general location of a target. The environment is much richer, featuring greater destructibility, improved visual quality and variety, weather effects, and a wider range of actions and animations for NPCs, among other things. Another remarkable ability known as Biobomb can be used to cause large scale destruction of multiple targets. Combat, movement and dodging system have been improved substantially. However the Musclemass ability has been replaced by the new Tendril power. The gameplay of Prototype 2 is similar to the first game. Heller sets out to foil Blackwatch and Gentek's operation in anyway he could. In order to help Mercer, Heller had to develop his abilities. Mercer claims that he wouldn't be able to take down the two factions without help. Blackwatch and Gentek were using New York for testing bio-weapons. He's then confronted by Mercer who manages to convince Heller that he was not responsible for the viral outbreak. Heller awakens in one of Gentek's research facilities and manages to escape. Impressed by his actions, Mercer infects Heller with his own strain of the Blacklight virus as he believed him to be the perfect lieutenant in spreading the virus beyond Manhattan. A fight ensues between the two, leading Heller attacking Mercer multiple times only to be thrown back. On one such mission into the Red Zone Heller's team is killed and he was confronted by Alex Mercer. He heads out on a suicide mission into the heart of the Red Zone with the intention of dying in action and taking as many abominations as he can with him. He discovers that his wife and daughter have been killed, sending him into a downward spiral of grief and rage. James Heller returns to the city, once his home, following his dismissal from a war in the Middle East. 14 months after the Blacklight being Alex Mercer saved the infected New York on his quest for redemption, Sgt.

Prototype 1 and 2