Jimmy Livingston is a boy born without an immune system. Because of this, he is forced to live in a bubble dome in his bedroom, which has led students at a local high school to nickname him Bubble Boy. Because of his condition, Jimmy's extremely religious mother forbids him to leave the bubble dome, only allowing him Highlights magazine and the Land of the Lost television show as recreation. When Jimmy discovers that a new girl, Chloe, has moved in next door, he is immediately taken with her. They immediately become fast friends, much to Mrs. Livingston's jealousy. They develope a close relationship with each other and Chloe tries to come into his bubble. Jimmy is too afraid and won't let her. One day, Chloe announces that she is leaving for Niagara Falls to marry the boorish rock-star Mark. Jimmy becomes upset and demands that she leave. Furious and sad at the same time, Chloe leaves him a present and disappears. Jimmy opens the present to find it is a snow globe that says "I Love You". Overcome with guilt for having driven Chloe away, Jimmy builds a mobile bubble suit and sneaks off into the night, determined to stop the wedding.
Throughout his journey to Niagara Falls, Jimmy meets many zany and odd people, including the Bright and Shiny cult, The Dr. Phreak traveling sideshow circus, Slim the biker and his gang of motorcyclists, and Pushpop the Indian ice cream man. In the end, Jimmy stops the wedding and takes off his bubble suit so he can finally touch the girl he loves. Jimmy's mother confesses that Jimmy has had an immune system since he was four years old, but she hid this fact from him in order to keep him all to herself. Jimmy forgives her, then grabs Chloe and kisses her. Jimmy and Chloe get married with all of their new friends in attendance. Then, Pippy and Pappy drive the two of them to their honeymoon.