The house that old man Nebbercracker owns is alive and is swallowing whole anything that comes close to it. Three neighborhood kids DJ, Chowder, and Jenny decided to plan an attack on the house on Hallows' Eve. There plans go array when police officers catch them attempting to break into the house and place the kids in the back of a police car. However, the house swallows the police officers and then swallows the police car holding the children. Now that the children are in the belly of the beast, they have to find a way to put a stop to this monster house.
In Monster House players take on the role of one of the three children as they explore the house and try to escape. Each child is armed with a water blaster and a melee attack to take out enemies, although their weapons have limited ammo and require refilling. Players can also find special items like keys, pop cans for health, and arcade tokens to play games like Thou Art Dead. The bathrooms are safe zones where players can save their game, while finding toy monkeys unlocks in-game art that can be viewed in the Gallery mode.