Homer is suffering from insomnia due to stress about his age. In an attempt to heal, the family takes a vacation to Florida. Little do they know, it is spring break when they arrive. After Homer accidentally kills the town alligator mascot, the family must go into hiding to avoid being arrested.
Homer gets a magazine in the mail that's loaded with personality tests, and he relentlessly quizzes his friends and family with them. Later on he takes his own test, which determines how long he has left to live. Unfortunately, Homer's less than stellar health and eating habits add up to only three more years to live. Marge suggests a few lifestyle changes to make that number go up. Naturally, Homer is against that and has a mental breakdown, developing insomnia and losing his sanity. He almost causes the Power Plant to be closed down when he asks the safety inspector to hide him, wearing nothing but a burlap sack. The plant's psychiatrist recommends Homer go on a long vacation for quiet recuperation, so the family head off to a town in Florida. Unfortunately, when they arrive it is Spring Break, one of the loudest weeks of the year. Marge wants Homer to stay in his hotel room, but he escapes to party at a Kid Rock concert on the beach. Homer becomes a nuisance at the party, annoying the audience, Joe C., and Kid Rock.
Homer wakes up the next day, rushing outside ready to party, but spring break is over: The students are returning home.
Homer tries to keep the party going, dragging the family along with him. He rents an airboat and they go through the swamp, accidentally running into the town's mascot, an alligator named Captain Jack. Despite the fact that Homer is the sole guilty culprit, the whole family is arrested for killing the alligator. They flee from the Sheriff, and head for a railroad crossing just as a freight train is going by. Although Homer is able to dodge the train, their car is hit by an Amtrak train travelling in the opposite direction, and pushed several miles down the tracks. The Simpsons end up at a secluded diner, where they work until the sheriff tracks them down and arrests them.
The whole family is sentenced to life in prison as well as forced labor. One night they try to escape but ultimately fail. However, before the family can be arrested again, Captain Jack appears - He had only been stunned by the boat's impact. The family is acquitted, but they are banned from entering Florida again. For their next trip, the family plans to go to North Dakota, the only state other than Arizona (which Homer complains "smells funny") the family is allowed to enter.
Kill the Alligator and Run was met with universally negative reception. It is often cited as one of the worst episodes of the show. In 2006, Nohomers.net named this the worst episode in the history of the show. Some fans have asked for the events of this episode to be made non-canon.