Alex Mercer has a problem or a gift - depending on the view. Thanks to a virus in his system he has several deadly powers and can change his appearance into any person he consumes which basically means the same thing as brutally killing the person he wants to be. Of course Alex didn't voluntarily get this "enhancement". Instead he was part of a genetic experiment at a company called Gentek. Having lost his memory about what exactly happened, he is now both looking for vengeance as well as his past. The second specimen, Elizabeth Green, on the other hand meanwhile infects more and more parts of Manhattan Island with a transmutation of the virus which converts people either into mindless zombies or brutal monsters.

Prototype is an open-world game similar to Grand Theft Auto IV where the player controls Alex through a 3rd-person-view. He is able to freely roam about Manhattan Island with iconic scenery like Central Park and Times Square. But instead of stealing cars and mugging old ladies, Alex feels more like going the Spider-Man route. By sprinting against a wall, he is able to climb and jump up to the roof fast. Thanks to his supernatural jump ability and his invulnerability to falling damage, he can then traverse the city from above instead of making his way through rush hour. Of course monsters like hunters as well as the military have the means to reach him even up there. To defend himself, Alex has several powers at his disposal. He can lift heavy objects and throw them at enemies, making it easy to take down even a full-blown helicopter. He also has the already mentioned ability to shape shift into any person he manages to grab and consume. When done without being seen, it removes the heat from Alex and will, just as hiding does, eventually put his human pursuers back to sleep. The monsters on the other hand will keep at him. It also enables him to enter areas he couldn’t access before. Other powers include claws, a shield, fists like boulders that make for a good punch and powerful lash. At any time Alex can only use one of those powers and he has to unlock them first. This is done by investing the evolution points he gains for killing enemies and fulfilling objectives into upgrades.

Divided into several categories, these upgrades increase for example his sprint speed, give him new abilities like said powers or enable him to do new moves like gliding through the air instead of just falling straight down. In addition some abilities like driving a tank or improving his ability to handle normal weapons can only be learned by consuming specific persons marked with a symbol over their head. This is also necessary to replenish his health and to uncover the Web of Intrigue. The Web of Intrigue fills in the blanks on Alex’s background and what happened to him at Gentek. Some pedestrians, military personal or police had more or less direct contact with Alex or the project he was part on and if he finds and consumes them, a short cutscene shows what he learns from that person. To keep an overview of his progress, the player can access a detailed map from the menu. There he can not only rewatch every movie but can also see what information connects with others, giving the player an understanding how every piece of the puzzle is connected.

If the player isn’t doing the missions of the main storyline or destroying military bases or hives, he can find several different kinds of mini-games in the city. Ranging from kill/consume missions and waypoint races over the roof tops to fighting small skirmishes on either the side of the military or the infected. In any case the player gains additional evolution points depending how well he did. These mini-games are unlocked by progressing through the story line as well as by getting a gold medal in a mini-game. Another past-time that grants evolution points is the search for landmarks and hints hidden around the island. The more the player collects of these, the more evolution points he gets for it.