The Simpson family is on a plate, as part of candies distributed on Halloween at a house. Barterfinger is afraid of being taken, Marge Bar comforts him saying he's always the last taken, and Oh Homer! saying even a box of stale raisins gets taken before him. Nelson's Crunch and Kirkish Taffy get taken, and Lisa the apple complains about no one ever wanting the apples, as people are afraid of razor blades being inside her. Marge comforts her saying they take them only when dipped in caramel, to the apple's disgust. Shauna takes Senior Mints, after Homer moved aside, and eats its contents.
The next day, the family are the only ones left, and they get placed on a shelf when the family remove the Halloween decorations, where they find a chocolate Easter bunny, that tells them they'll be left there forgotten. Seeing his discomfort as no one ever takes him, Homer starts eating him. Marge tries to stop him, but he tells her chocolate doesn't feel anything, and resumes eating it, with the rest of the family joining in when he eats the bunny's mouth to shut it up. The camera pans to the wall, where The Simpsons Easter Special is written, but the chocolate from the bunny splatters all over it, covering the words, and dark chocolate resembling blood spells out "Treehouse of Horror XXVIII".
On a pre-Christian temple site in northern Iraq (a parody of the opening scene of The Exorcist), a Pazuzu statue is dug up and sent through Amazon to the Simpsons home due to Homer accidentally ordering it, thinking it said “pizza”. After Homer sings a very disturbing lullaby with glowing red eyes, the statue is left on Maggie's bed as the demon within it possesses Maggie, with the possessed infant making her presence known during the cocktail party that Homer and Marge are hosting downstairs. The demon kills a complaining Helen Lovejoy before locking everyone in and then killing Dr. Hibbert while revealing that he is cheating on his wife. Ned Flanders tells the Simpsons that Maggie needs an exorcism before being killed himself from being beaten up and choking. An Irish priest arrives soon after, and performs the exorcism that purges the demon from Maggie, but the demon ends up possessing Bart, which he fearfully regrets, declaring that Bart has the evilest soul he's ever seen and is "worse than David Schwimmer".
In a parody of Coraline, Maggie is still recovering from Pazuzu while starting to violently vomit all over the dinner table, eventually flooding the kitchen with puke. In Lisa's room, Snowball V (Neil Gaiman) takes her through a secret tunnel that brings her to another version of the family, with pink buttons instead of eyes on their faces. While the alternate family are like a dream, Lisa runs back to her world in terror when she learns they want to sew buttons on her eyes so she can remain with them forever. Lisa reconsiders the alternate family's offer after Homer had killed a snake with Lisa's saxophone.
A few days later, the family finally realizes Lisa is missing with Homer accepting it and saying Maggie that gets Lisa's room and clothes, while Bart gets her homework. Upon hearing this, Bart escapes through the door and is accepted in the alternate reality. After Marge follows after her children, Homer follows suit and a meeting with the alternate family results with him killing the alternate Bart while alternate Homer injures himself on a pair of scissors trying to avenge him. This infuriates alternate Marge as she transforms into an eight-legged spider-like creature to attack Homer, who decides to take advantage of the situation to benefit himself: bringing the surviving members of the alternate family home with his alternate counterpart attending parent-teacher meetings while alternate Marge does the chores and guards the house. Lisa accepts this outcome, claiming that it could have been much worse.
An opening scene features Lisa warning viewers about the following segment’s disgusting content. The episode then begins when a Homer remains home while the rest of the family go on vacation with Patty and Selma. Homer gets comfy, but ends up eating his food supplies, ending up with only vegetables before finding a frozen hot dog. Losing the hot dog to Santa's Little Helper in the process, Homer accidentally cuts his finger off while grilling. He cooks the finger and eats it. He discovers how tasty it is, losing interest in other food when invited by Ned for lunch, and starts cooking parts of his body before his family come back. They become suspicious with Homer constantly wearing oven mitts to hide his severed fingers, being 20 pounds thinner, and walking with a limp. When Marge discovered Homer's self-cannibalism one night while he was frying his own severed leg, she takes him to an addiction counselor for help, but Mario Batali, in search for new ingredients, convinces a despondent (and now missing the entire lower half of his body) Homer to cook his remaining body parts as ingredients sold at Chez Homer and several other restaurants across Springfield. Carl mentions that they are also eating Barney Gumble, Comic Book Guy, and horse meat. In Heaven, Homer comments to Jesus how he now shares people eating parts of his body with him, as the Springfield residents have turned into cannibals.