DJ Walters spies on his elderly neighbor, Horace Nebbercracker, who confiscates any item landing in his yard. DJ’s parents go to a dentist convention, leaving him in the care of babysitter Elizabeth “Zee”. DJ’s best friend Charles “Chowder” visits, accidentally losing his basketball on Nebbercracker’s lawn. DJ is caught by Nebbercracker while recovering it, who rages at him before apparently suffering a stroke and being taken away by an ambulance. That night, DJ receives mysterious phone calls from Nebbercracker’s house with no one on the other end. DJ eavesdrops on Zee’s boyfriend Bones, who tells Zee about losing his kite on Nebbercracker’s lawn when he was young and that Nebbercracker supposedly ate his wife Constance. Later, Bones is driven out by Zee after he gets too fresh. He sees his kite in the doorway of Nebbercracker’s house, but is consumed while retrieving it.
The next morning, a girl named Jenny is selling Halloween snacks. DJ and Chowder see her going to Nebbercracker’s house, and rush out to catch her before she is eaten. Jenny calls the police, but officers Landers and Lester do not believe their story.
The trio seek advice from Reginald “Skull” Skulinski, a self-professed expert on the supernatural. They learn the house is a “Domus Mactabilis” (Latin for “deadly home”), created when a human soul merges with a structure. The only way to kill the house is to destroy its heart. They conclude that the heart must be the furnace, as DJ realizes the chimney has been smoking since Nebbercracker supposedly died. Chowder provides a cold medicine-filled dummy that should cause the house to sleep while they douse the furnace. Their plan is thwarted when Landers finds the medicine stolen from Chowder’s father’s pharmacy inside the dummy; the three kids are arrested. Landers and Lester place the trio in their car while they examine the house. The house consumes the police and the car. DJ, Chowder and Jenny escape the car but are trapped in the house.
The house falls asleep and the kids explore. They fall into the basement, finding toys accumulated from Nebbercracker’s lawn, as well as a cage door that opens to a shrine containing the body of Nebbercracker’s wife Constance the Giantess, buried in cement. The house realizes they are inside and attacks them. DJ, Chowder and Jenny force the house to expel them by grabbing its uvula. Nebbercracker arrives home, revealing that Constance’s spirit inhabits the house. As a young man, Nebbercracker met Constance, an unwilling member of a circus freak show who hated children, falling in love with her despite her obesity. After helping her escape, they married and began building the house. One Halloween, as children tormented her due to her size, Constance tried chasing them away with an axe, but lost her footing and fell to her death in the basement with the cement burying her body. Nebbercracker finished the house after Constance’s death, knowing it was what she would have wanted. Aware that Constance’s spirit made the house come alive, Nebbercracker kept people away for their safety by pretending to hate children.
DJ tells Nebbercracker it is time to let Constance go. Enraged, the house breaks free from its foundation, chasing the group to a construction site. Nebbercracker attempts to distract the house so he can throw sticks of dynamite in, but the house notices and attempts to eat him. Chowder fights the house off with an excavator, causing it to fall into a pit. DJ is given the dynamite, and he and Jenny climb to the top of a crane while Chowder distracts the house. DJ throws the dynamite into the chimney, destroying the house. The trio see Nebbercracker with Constance’s ghost before she fades away. DJ apologizes to Nebbercracker for the loss of his house and wife, but Nebbercracker thanks DJ and the kids for freeing him and Constance from being trapped for 45 years. That night, children in their Halloween costumes are lined up at the site of Nebbercracker’s house, where DJ, Chowder and Jenny help him return the toys to their owners. Jenny’s mother picks her up, and DJ and Chowder go trick-or-treating, which they previously felt they were too old for. Those who were eaten by the house emerge from the basement.