Prototype 2 is an action game set in an open world environment and it is the sequel to Prototype. At the end of the first game protagonist Alex Mercer managed to destroy the Blacklight virus that infected him and granted strange powers, but he was thought dead. Fourteen months later however another outbreak hits New York City. It is the third outbreak in history and the city is renamed New York Zero. The protagonist of this game is James Heller, a sergeant in an Iraq tour who receives phone calls from his wife Colette. She fears for her safety and their daughter Amaya as new reports about an outbreak start pouring in. Mutated people and creatures are roaming the streets again and the Blackwatch organization reappears to contain the outbreak violently. Returning home Heller discovers both are dead and he rejoins the army to fight what is now called the Mercer virus, as Alex Mercer initially reappears as an antagonist in this game. Soon however Heller is also infected by a strand of the virus and receives the same powers as Mercer. He is taken in by Gentek for tests, but eventually manages to escape and flees to Mercer who explains him that Blackwatch and Gentek are really behind the virus. After the introduction the main game starts at the moment Heller decides to pursue Gentek while he stays in contact with a priest called Guerra.

The game is set in New York Zero which has been divided into three zones based on the infection rate: red, yellow and green. That means there are also areas where Heller can freely roam among regular civilians as long as he does not display his powers. There is a main storyline with quests to pursue but also a large amount of freedom in exploration. He can eventually hack into the military grid Blacknet that details all military operations. From there he can choose his own missions in pursuit or the organization rather than being told to do quests.