Lisa awakens one morning with a potent case of the blues. In school, her musical stylings are stifled by the music teacher Mr. Largo, and she refuses to play dodgeball, claiming to be too sad. Her teacher notices her sadness and sends a note home to her parents. Homer and Bart, meanwhile, are playing a video boxing game. Undefeated with forty-eight wins, Bart takes only one round to knock off the head of Homer's boxer. While Homer is down for the count, Marge gives him the note from Lisa's teacher. Nothing her parents say can bring Lisa out of her depression.
Hearing distant music, Lisa sneaks out of her room to follow it. She finds a soulful saxophone player, Bleeding Gums Murphy, playing some hard blues. Murphy teaches Lisa how to express her sadness on the sax.
Afterwards, Marge drops off Lisa at school and tells her to smile no matter what she feels inside. She later sees Lisa hiding her true feelings and classmates taking advantage of her and tells Lisa that it is best to be herself. When Lisa hears this, she feels happy again.
Meanwhile, Homer takes lessons from a local video game wizard for a rematch with his son. Just as he starts to win, Marge unplugs the TV to announce Lisa's recovery. Seizing the opportunity to maintain his undefeated status as boxing champ, Bart gleefully announces retirement from the ring. Afterwards, the Simpsons visit a jazz club to hear Bleeding Gums Murphy sing a blues number written by Lisa.