As Lisa gets kicked out of class by Dewey Largo, she goes on the street, where Sideshow Mel and Lindsey Naegle are watching, enjoying her music, but, after Ralph comes out with a tuba stuck on his head, Largo tells Lisa she should quit playing her saxophone, making her cry and trying to make her give up on her dream.
At the school playground, Bart makes a prank on Jimbo but is caught by Kearney and Dolph, so they dress him as Little Orphan Annie and they make him sing at the cafeteria, while kids start throwing food at him.
At home, Marge tries to make her change her mind, but she can't play in front of Homer, Grampa and Maggie. At the computer, she finds out she has the Yips disorder.
A parent of Marge, Eunice Bouvier, invites them to Florida for her 100th birthday, so they board the plane to Gainesville, but when Homer causes a ruckus in the plane, the pilot changes destination to New Orleans, leaving Eunice alone for her birthday.
On arriving they split up, Marge with Bart and Maggie and Homer with Lisa. Homer tries to cheer her up but fails and they go around the city, with Homer eating stuff everywhere, stuffing himself up.
Marge brings Bart to a voodoo shop, Madame Midnight House Of Voodoo, where he buys voodoo of the bullies, while Marge prays for a normal trip for the family without their demons.
To help Lisa find her confidence again in jazz, the statue of Louis Armstrong comes to life and gives her advice, including following what his father says.
While Bart starts using voodoo on the bullies, Homer brings her to The Spotted Cat Music Club, and is invited to the stage by Bleeding Gums Murphy's nephew, who knows her thanks to a picture of his uncle and her playing on the bridge.
The nephew says Murphy said she was the most promising young musician he ever met, and that gives her incentive to play and gets her out of the Yips disorder. At home, Lisa is back to her playing, and is visited Louis Armstrong's ghost too. At the end, Homer, Lisa and Bart eat beignet at Cafe Du Monde.