Manhunt casts you as James Earl Cash, a prisoner on death row. You are led down a corridor where you are about to receive a lethal injection. The needle goes in. You wake up hours later. A mysterious voice tells you to stick in the nearby earpiece, and explains that the "lethal" injection was just a heavy sedative. The man, later identified as Starkweather, turns out to be a director of snuff movies, where the people are really killed. He explains that if you follow his directions, manage to kill people and survive, you'll earn your freedom. This begins James Earl Cash's journey.

Throughout the course of the game, you'll have to make your way through different locales, such as a city and a mall, while killing gangs. You'll face lots of different gangs, from The Hoods and The Skins to tougher gangs like The Innocenz. Gang members carry weapons ranging from pistols and shotguns to knives and glass shards.

Manhunt is primarily a stealth game. You'll have to hide behind walls, flatten yourself against walls, crouch, hide behind objects, and walk to avoid attracting attention. You can also throw glass bottles to create a distraction, or you can punch surfaces and yell to get gangs to come to you.

You have a variety of weapons at your disposal, from the traditional, such as the shotgun and uzi, to the disgusting, such as a sickle and plastic bag. Each weapon has three different ways of attacking, depending on how long you hold the button. A quick attack will do the job, a medium attack will be bloody, but a high attack, requiring the longest amount of time, will earn you the most points, and will allow you to see your kill in a cinematic style, with blood splatting on the camera, and gurgling noises.

Manhunt also lets you use a USB headset, such as the one that came included with SOCOM: U.S. Navy Seals. With the headset, you will hear Starkweather speak into your ears instead of through your speakers, and you will be able to shout into the microphone to attract gangs instead of pressing a button.