Homer, Bart and Lisa are cleaning the back garden when Marge orders the family inside to watch TV. On Kent Brockman's Channel Six "Oops Patrol" segment, he displays a humorous headline ("Mayor Displays Erection to Cheering Crowd"), noticed and submitted by Marge, for which she received a free T-shirt. When Doctor Hibbert offers Marge special health treatments such as a new heart because he likes her shirt, an envious Homer attempts to find his own funny headline so he too can win a T-shirt, to no avail.
Homer spends the following night with newspapers plastered over his bedroom wall, exhausting himself in his search. He finds an attractive article entitled "World's Biggest Pizza". Oddly enough, the first letters of the first five lines spell "HOMER". Homer wakes Marge and tells her that someone or something is communicating with him, telling him to meet them at Fourth Street Overpass at midnight. He discovers that it is that day's paper, and wakes Bart up so they can both go. When they reach the overpass, the mystery person arrives, frightening Homer and Bart. Bart tries to attack with a lunging karate kick, only to land right through and into a sweater with the words "World's Best Grandson". The stranger then reveals herself to be Mona Simpson, Homer's mother, and Homer hugs her after first hugging a bum trying unsuccessfully to steal his wine.
Homer reunites with his mother again. At the Overpass Diner, she apologizes for the cloak and dagger, and explains that it was because the government is still hunting for her because of her 1960s crime of sabotaging Mr. Burns' germ warfare lab. Her liberal links at the Springfield Shopper published the story of the giant pizza to lure Homer, knowing that pizza was the first food Homer choked on. Bart questions why Mona came back, and she reveals that it was because of nostalgia aroused by a macaroni pencil case Homer had made for her when he was five. Just then Chief Wiggum, Lou, and Eddie arrive at the diner, and Lou recognizes Mona. Waitress Hora lets Homer, Mona, and Bart escape through the back after they increase her tip. In the car, Homer vows not to let the cops get Mona again, and immediately rams into the police station, where Mona is arrested. Despite the fact that Mona had done many useful community service acts, Mr. Burns insists she be put on trial. When the trial goes unsuccessfully, Homer is put on the stand and, after a long clueless pause, he miserably gives a heartfelt request that they do not take his mother away from him again. The jury, deeply moved, decide to acquit Mona. Mr. Burns is infuriated by the outcome, which contradicts his belief that justice should favor the rich.
A montage follows of Mona catching up on Homer's missed childhood; giving Homer a bath, watching Homer in the school play, knitting for Homer, teaching Homer how to ride a bike, and seeing a reenactment of the birth of Bart. Mona also catches up with Lenny, Carl, and Moe. To make Mona more welcome, Homer steals a whole room from Ned Flanders's house so she could have her own private bedroom. Mr. Burns renames his Germ Warfare Laboratory the "Grandma Simpson Peace Museum and Kid-teractive Learnatorium", to a crowd of cheering onlookers. Mr. Burns asks Mona to be the first to sign the museum's guest book. As she signs, she unwittingly mentions she had been signing false names when visiting state parks, and prodded by Burns, says she also did so at national parks, which is a federal offense. The FBI, park rangers and other Federal agents jump out and arrest her for supplying false information on a national park register. They handcuff Mona, and take her away in a car. A distraught Homer runs after the car, whose drivers keep stopping periodically again and again to taunt him. Back at home later, a miserable Homer reminisces about the times he and Mona had caught up on, looking over photos of him and Mona, including one in which Homer strangles Bart as Mona strangles Homer. Lisa tells Homer she disagrees with what the government did with Mona, and unintentionally gives Homer the idea to break Mona out of prison.
The next day, as the bus transfers Mona and other female convicts to prison, Homer and Bart trick the bus into pulling over by changing a sign overhead to display a warning of a snowstorm ahead (despite the perfect weather). As the drivers get off to put chains on the tires, Homer steals the bus and liberates all the convicts except for Mona, who all sarcastically promise to return to prison. Suddenly, police cars appear and give chase. Mona does not want Homer to be imprisoned and leave his children like she did, so she electrically shocks him and pushes him out of the bus onto an abandoned bed. As the bus nears a cliff with the police in hot pursuit, Homer watches in horror as the bus flies off the cliff into a lake, blows up, and is covered by a rockslide.
The Simpsons hold a funeral for Mona and pay their respects, but then the coffin suddenly slides away and into a forest and a grief-ridden Homer vents his frustration by kicking down Frank "Grimey" Grimes' tombstone. Later at night, he pores over newspaper headlines, hoping his mother survived and left another message for him, since her body was not in the coffin (Homer says it was instead filled with "Last week's garbage"). He finds a random article in which the first letter of each row spells out "IMOK" over the front and back side of the page. Taking this to be another message from his mother and reassured by his family (who believe she is dead), he goes to sleep. However, he overlooks an article about a giant taco, in which Mona encoded a long message that explains that she escaped from the bus before it crashed and hitched a ride out of town.