In Prototype, the player takes the role of Alex Mercer, a man who wakes up on a morgue table as a mutagenic virus is unleashed at New York Penn Station. The virus quickly spreads, changing citizens into feral creatures while buildings are converted into hives to mass produce infected and Hunter creatures. In the meantime, the island of Manhattan is locked down tight under quarantine while Marines work to contain the catastrophe by setting up bases across the city under the secret management of a mysterious organization called Blackwatch. However, the spreading infection is a secondary problem. Mercer awakens with no memory of his identity, his past or the origin of his deadly powers. Therefore, his primary mission is to find out who is behind it all (his creation, the infection, etc.) and get revenge against them. To this end, Mercer will kill and consume everyone that gets in the way until he reaches the top of the command chain.

Players have a long list of abilities at their disposal, which can be chained into powerful combinations. Basics include running up buildings, then jumping or gliding long distances. Anyone looking for an interesting tour of New York City may want to check out Prototype for the ability to climb up famous landmarks like the Empire State Building. There are also other benefits in touring the city, like ripping through Times Square while battling giant monsters. Combat moves make extensive use of Mercer's super strength, so he can kick enemies down the block or throw cars at attack choppers. His most devastating moves stem from his ability to change shape, which outfits his arms with weapons like claws provide him with armor, but he can also pick up any human weapons left lying on the ground to use against his foes. Mercer also has another core ability, which is to consume other creatures for health, and consuming humans allows him to take on their likeness, memories and skills for infiltration.

It's a good thing Mercer has all these powers, because everyone from the military to the infected are all out to kill him. In Prototype, with great power comes the license to be a super jerk. It's the player verses the entire city of New York and they're free to pretty much cut loose with their powers at any time, against any one. Lengthy engagements, like when the military is alerted to Mercer's presence, end with a status report listing all the damage the player has wrought. A civilian casualty number is shown, but players aren't penalized for it, leaving players free to do pretty much whatever they want. Changing shape in plain sight and throwing cars around will draw the attention of the military, which will call in tanks and attack choppers to help take you out. Some might find the situation beneficial, since having all the targets come to you is much easier than hunting them all down yourself. Progressing through the game's main story missions unlocks access to more powers, while completing skill based challenges earn Evolution Points (EP) to purchase new abilities, as does killing infected and military. The game provides a huge variety of ways to clear the streets of enemies, ranging from supercharged "critical mass" powers that will wipe out everything within a radius of Mercer, to using a tank to roll over anything that happens to be in the way.