Up to three simultaneous players control gigantic monsters: George, a King Kong-like gorilla transformed from human form by an experimental vitamin, Lizzie, a Ymir-like[4] dinosaur/lizard transformed by a radioactive lake, and Ralph, a giant werewolf, transformed by a food additive. The monsters must raze all buildings in a high-rise city to advance to the next level, eating people and destroying helicopters, tanks, taxis, police cars, boats, and trolleys along the way.[5]
The player can climb any of the buildings, punching them to pieces and reducing them to rubble. Non-playable human characters within the levels can also be punched or grabbed and food items can be eaten. The player's monster receives damage from enemy bullets, sticks of dynamite, shells, punches from other monsters, and falls. Health is recovered by eating food items such as fruit, roast chicken, or soldiers. If a monster takes too much damage, it reverts into naked human form and starts walking off the screen sideways, covering its body with its hands. In this state, players can be eaten by another monster. If the player continues, the human mutates back into the monster or (if the human walked off the screen) flies in on a blimp (but has lost their score), with a full life bar.
Smashing open windows generally reveals an item or person of interest, which may be helpful or harmful. Helpful items include food or money, while dangerous ones include bombs, electrical appliances, and cigarettes. Some items can be both; for example, a toaster is dangerous until the toast pops up, and a photographer must be eaten quickly before he dazzles the player's monster with his flash, causing it to fall. When a civilian is present waving their hands at a window signaling for help, a player's points rapidly increase when the person is grabbed. Each monster can hold only one type of person: George can hold women, Lizzie can hold middle-aged men, and Ralph can hold businessmen.
Rampage is set over the course of 128 days in cities across North America. The game starts in Peoria, Illinois and ends in Plano, Illinois.[6] In Plano, players receive a "mega vitamin bonus" which heals all the monsters and provides a large point bonus. After this, the cycle of cities repeats five times. After 768 days, the game resets back to Day 1. As game developer Brian F Colin stated "the hardware couldn't support that much art and we never figured anyone would get through 768 levels".[7]
Some of the home port versions of the game start in San Jose, California and end in Los Angeles, California after going all around North America. The rampage travels through two Canadian provinces and forty-three United States states. Only Connecticut, Delaware, Mississippi, New Hampshire, Rhode Island, South Carolina, and Vermont are spared from the monster rampage.