Jimmy Livingston (JAKE GYLLENHAAL) is a young man who's lived his entire life in his bedroom in a protective, germ-free bubble due to having an immunity deficiency since birth. While his parents (SWOOSIE KURTZ and JOHN CARROLL LYNCH) have fulfilled most all of his needs, Mrs. Livingston's well-intentioned but misguided ways have left him with a warped sense of reality.
His best friend is Chloe (MARLEY SHELTON), the pretty girl next door, and while the two of them are very close, she decides to marry a local jerk, Mark (DAVE SHERIDAN), her boyfriend from the past several years. Realizing he must tell Chloe how he feels about her, Jimmy then builds a mobile bubble suit and proceeds on a cross-country trip to stop the wedding that's to take place in just three days in Niagara Falls.
Unfortunately, Jimmy has no way to get there, but then finds various people willing to help him out or at least take him part of the way. Among them is a busload of cult members from the Bright and Shiny sect who are off to see their leader, Gil (FABIO), as well as Slim (DANNY TREJO), a macho Hispanic biker. After various moments and adventures with them, he runs into Dr. Phreak (VERNE TROYER) and his traveling "freak" show, as well as Pushpak (BRIAN GEORGE) an Indian ice cream and curry truck driver and Pappy (PATRICK CRANSHAW), an old taxi driver.
As the hours count down to the wedding and Mrs. Livingston sets out to find and retrieve her son, Jimmy does what he can to make it to the nuptials and stop Chloe from marrying Mark, all while finally experiencing the real world outside his normal, sheltered life.