Traditional horror movie characters such as Frankenstein's Monster, the Mummy, the Wolf Man, and Dracula roam the streets of Springfield on Halloween night. After they are teased by Dolph, Jimbo, and Kearney, they get new, more modern costumes from a Halloween store, with Frankenstein's monster as SpongeBob, Dracula as Iron Man, The Wolf Man as Harry Potter and The Mummy as Captain Jack Sparrow. They then go to an adult Halloween party thrown by Homer and Marge, but are soon confronted by their wives, who are angry that their husbands lied about going out to kill children tonight. Homer tries to intervene as the wives begin to assault their husbands, only to be decapitated, and his eyes are then replaced with two red x's, the title of the episode then appears onscreen.
In a parody of Strangers on a Train, Lisa wants revenge after being sent to detention by Ms. Hoover for disrupting class as she claims another student topped her through a tutor. Bart hatches a "criss-cross" plan and tells Lisa that if she pulls a "ding-dong ditch" on Mrs. Krabappel, he will do the same to Ms. Hoover. Lisa thinks this means ringing the bell at Mrs. Krabappel's apartment and leaving. However, Lisa soon learns that Bart meant for her to kill Mrs. Krabappel (and dump the corpse in a ditch), as he has killed Ms. Hoover. Bart attempts to coax Lisa into killing Mrs. Krabappel with a paper cutter, but she refuses. Eventually, Bart decides to blackmail her into it with help from Willie, who would frame Lisa for the decapitated Skinner to honor his side of the "criss-cross" in which Bart killed Skinner. Realizing that Bart would frame her for these incidents, Lisa tricks him into belief that she was submitting at his will only to get a knife from his hands and attempts to kill Bart in self-defense, beginning a chase sequence. Bart finally finds shelter at a crowded playground carousel, but is left at Lisa's mercy when the other children leave to get ice cream. Lisa, however, recognizing that she would not be better than Bart, says she will never be a murderer, and attempts to throw the knife away. The knife cycles out of control and ends up nailing Bart in the head just as Mrs. Krabappel appears, pleased at his death. Despite her shock for accidentally killed Bart, Lisa agrees that it is better this way and she and Krabappel walk away smiling, leaving the murdered Bart to spin around on the carousel.
Krusty the Clown introduces a new version of his Krusty Burger, the Burger2, made from cattle that have eaten other cattle in their feed. Upon eating a burger on live television, Kent Brockman begins to comment on the taste before turning, gray, red-eyed, and cannibalistic, starting a chain reaction of people getting eaten. Twenty-eight days later, Springfield has become overrun by zombies. The Simpsons are established to be one of the few survivors.
One day, Bart, tired of eating fruit, escapes from his family's barricaded house and eats one of the burgers, but turns out to be immune to its effects. Over the phone, a besieged Dr. Hibbert tells them that Bart's immunity may be the key to developing a cure to the epidemic and that they must bring Bart to a so-called "safe zone" outside the city. The Simpsons are attacked after a failed attempt to sneak out but are saved by Apu, driving an armored off-road truck. Apu explains that he was never infected because, as a vegan and a Hindu, he is morally opposed to eating anything that was once an animal, and, as a convenience store clerk, he is "armed to the teeth" in case of a store robbery or a zombie apocalypse.
The group tries to leave Springfield, but Apu crashes the truck on top of a pile of smashed cars. Apu goes to push the car off the pile, but the Simpsons drive away thinking Apu sacrificed himself, when he actually wanted the Simpsons to wait for him. After Apu is killed, the Simpsons drive on but run out of gas, walking the rest of the way to the safe zone. During their journey, Homer is bitten by Mr. Burns, thus turning him into a zombie himself. The family decide not to kill him in the hopes of finding a cure. They reach the safe zone, where Bart – being immune to the virus – is worshiped as the "chosen one". However, the people there believe that cannibalizing Bart will save them from the virus. The Simpsons think of another solution: vaccinating the remaining populace by having Bart bathe in their food before eating it.
In a parody of Sweeney Todd: The Demon Barber of Fleet Street, in which is presented like a Broadway musical, Moe is lonely and upset that he does not have a girlfriend and is jealous when he sees Homer and Marge together. When Homer falls into the basement of the bar and is impaled by the microbrew pipes, his blood becomes the secret ingredient in Moe's new beer. Everyone loves this new beer, saying that it makes them feel warm, secure and cozy on the inside. Moe uses this to his advantage and woos Marge, tricking her into thinking that Homer came out of the closet as a homosexual and left Marge, when in reality, Homer is slowly dying from losing blood. Homer emerges, alive, despite being impaled by Moe's microbrew machine, hurls a dummy of Moe across the room, and reunites with Marge.
Then, the whole audience except for Kang and Kodos gather onstage and conclude the episode by singing "Number XX" Where Kang then shushes the audience, gesturing at Kodos, who has fallen asleep with the playbill over his helmet.