Seven years ago, Lisa wakes up Marge and Homer. Homer admires how awesome she is, offending Bart who stabs him in the leg with a pencil.
In the present, Lisa is writing an Harvard College admission essay and she starts writing her past.
She begins with her 7th birthday, showing how Marge gets Maggie addicted to pacifiers. The family and her teacher Ms. Myles forget her birthday, with Ms. Myles sending her to Principal Skinner after she gets sad on them celebrating Hubert Wong's birthday. Homer comes to get her and finally remembers it's her birthday, and coming home they find out Ned didn't forget and gifts her a tricycle. The family celebrates her birthday with a cake made of a cup of milk and some candles on it.
Next, Homer is working on an exercise bike and is having medical trouble. Lisa shows how the marriage with Marge is troubled, that nearly fell apart when she turned 14. The family this time remembers, and brings Leon Kompowsky to sing new verses for "Happy Birthday, Lisa" while Homer brings a cake with “Happy twelfth twelfth 12th birthday”, upsetting her.
Lisa returns home from school in the bus and discovers a letter in a suitcase while placing some packs in Marge's closet, saying that she left him and opened a bed and breakfast with the other kids, and a tablet with Artie Ziff mocking him for it. However, Marge hasn't left yet.
At dinner, Marge gets angry at Homer for drinking in front of the kids, and tells him to go to Moe's Tavern to drink. Marge goes to the kitchen to cry and Lisa is ready to take action. At the tavern, Moe now has artificial spider-like legs while Lisa enters to tell him that Marge is going to leave him and makes him promise that he'll stop drinking. He calls his sponsor to help him to stop, and it's Ned. He succeeds and the marriage is saved.
Harvard College sends in a drone to Lisa with her acceptance and it destroys other similar drones from other colleges. She goes to college and sets up her room, but is not happy in her first day. Bart cheers her up and then leave with the rest of the family, preparing for the new life, also meeting a new roommate that makes life in college better. We get to see a collage of scenes through her life, back to the first scene.
In the final scene, Homer, Lisa, and Marge sing a new version of "Those Were the Days" from All in the Family. Norman Lear enters the house telling Homer and Marge that he'll see them in court.
A final tour of Springfield is shown during the credits which plays the closing theme to All In the Family with the Duff Blimp saying "Stay tuned for Simpson and Son" (a spoof of Sanford and Son).