Kang and Kodos star in a fictional sitcom, entitled Keepin' it Kodos. In it, Kodos is preparing their boss' visit by cooking dinner: Homer on a baking tray (continually eating himself), Bart on a skillet, Marge and Maggie in pies and Lisa in a soup (with Bart seemingly being the only family member to be in pain). The boss gives the meal a delicious rating, but his stomach bursts, liberating Bart.

Kang and Kodos are given a hyper-galactic promotion, much to the aliens' delight. Bart is sad about the loss of his parents and sisters, but Kang and Kodos decide to adopt him, which comforts Bart. The theme song from Perfect Strangers plays as the Treehouse of Horror logo appears on the screen; an alien tentacle stamps the "XV" underneath which makes it say the title of the episode in the fashion of the Mark VII Limited company logo.

Trying to get his Frisbee from the roof, Homer throws a bowling ball that eventually hits Ned on the head. When Ned recovers in Dr. Hibbert's hospital, he has a vision of the good doctor falling out of a window to his death, which actually happens shortly afterward when Homer asks him to get his frisbee from the window ledge. In a parody of The Dead Zone, Ned realizes that he can see the deaths of people whom he touches; he saves Hans Moleman from falling down and has a vision of him getting chewed up by American alligators. In shock, he drops Moleman - right into an open manhole full of alligators. He also predicts the closing of the Rosie O' Donnell musical, but he "didn't need special powers to know that was coming!"

A later vision depicts him shooting Homer; when Homer finds out, he taunts Ned and even gives him Chief Wiggum's gun to shoot him with. Ned refrains from shooting Homer, and realizes he has changed the future, but then has another vision, this time of Homer blowing up Springfield by pressing the 'Core Destruct' button at the nuclear power plant. Ned tries to dissuade Homer from going to work, but Homer goes anyway because of ice cream cake for Lenny's birthday. Ned rushes to the power plant to stop Homer, but his warning is scrambled by static over the intercom, sounding as if he is encouraging Homer to press the button. In desperation, Ned grabs a nearby security guard's gun and forces himself to shoot Homer (thereby fulfilling the original prediction); but in his death throes, Homer presses the destruct button with his tongue. Ned has enough time to say "You stupid son of a..." before the power plant explodes and Springfield is destroyed.

Ned, The Simpsons, and their garage (which Homer was assigned to clean, leading Marge to believe he blew up the town specifically to get out of doing so) go to Heaven as angels and meet God, who proceeds to give Homer "what he deserves" - returning his Frisbee.

In 1890, London's prostitutes are being killed with swords in a series of unsolved murders by "The Muttonchop Murderer". Scotland Yard's Inspector Wiggum challenges master detective Eliza Simpson and her easily amazed, goofy assistant Dr. Bartley to solve the crime. Their first piece of evidence is a bloody sword found by a "proper-Cockney flower girl", Marge. Simpson takes the sword to an oddities merchant (Comic Book Guy), who recognizes the sword as part of a set he had sold, called The Seven Swords of Osiris. He goes to check his dusty record books to see who he sold the swords to, but is murdered by the killer. Looking at the ledger, Simpson and Bartley discover the swords were sold to C. Ebenezer Burns, an industrialist who "makes coal out of babies".

Bartley knows where to find Burns and tracks him down at Mao's Den of Inequity, an opium den. Burns instantly recognizes the sword, and tells Simpson that he sold them for opium to a "fat man with sideburns", and notices a man nearby who resembles the description, Homer. Simpson and Bartley chase him down and Homer gets caught by Wiggum, who happens to be at the opium den as well, to help his son Ralph go to sleep.

Simpson and Bartley congratulate themselves for solving the crime, until they find another body, Selma, stabbed by another Sword of Osiris. Bartley first dismisses the body as having been killed days prior, pointing out the body as bloated and the face rotten, though Selma is alive long enough to say it was just "5 minutes ago". Simpson takes the sword and recognizes a certain scent on the sword handle. The next day, just before Homer is hanged for the murders, Simpson arrives, declaring Homer innocent due to the smell of eel pie on the handle, which Wiggum loves to eat.

Officer Lou then reveals that Wiggum has muttonchops as well, exposing him as the killer. He starts to explain that he just wanted to come up with a case that Simpson herself could not solve, but then flees in a hot-air balloon stolen from Professor Frink, but it gets pierced by a steampunk-style flying saucer flown by Kang and Kodos, who consider Earth's air fleet as destroyed. It is then shown that the whole story was an opium-caused dream by Ralph, which Wiggum reveals is part of an even crazier and fantastical dream that both of them are in.

At the "Invention Expo", Professor Frink creates a machine that shrinks objects. Maggie crawls inside a giant pill, thinking that it is a ball pit, which is miniaturized and swallowed by Mr. Burns. When the rest of the family realizes what has happened, they agree to be shrunk within a craft and injected into Burns' body. Homer is the craft's captain, Lisa is in charge of science and research, Bart is in charge of security, and Marge is in charge of helping the deeps of the science.

When Homer refuses to follow Frink's instructions, the ship gets stuck in Burns' heart. The crew manage to get the ship free from the outside and are able to reach the stomach by catching a ride on a nerve impulse, which Lisa calls "the body's information superhighway". They manage to save Maggie, but Homer is forced to leave the ship and save the rest on his own when their craft does not have enough power to save them all due to the addition of Maggie's extra weight.

Homer becomes initially despondent at his family is forced to leave him behind, but finds consolation in finding a marshmallow in Burns' stomach. The submarine successfully escapes, but there is not enough time to save Homer, who instantly returns to his original size inside Burns' skin, putting them both in extra pain. Even though Homer complains that Burns needs several extra holes, Burns is confident that things will work out.