What happens when a person decides that life is merely a state of mind? If you're Betty, a small- town waitress and soap opera fan from Fair Oaks, Kansas, you refuse to believe that you can't be with the love of your life just because he doesn't really exist. After all, life is no excuse for not living.

At home one night watching a videotape of that day's episode, Betty watches raptly as her favorite character, Dr. David Ravell, stares up at the moon and says, "I know there's someone special out there for me." Betty feels as if he's speaking directly to her. That is, until her husband comes home with two men to negotiate a shady business deal. As she tries to watch her show, Betty becomes an accidental witness to this deal going fatally awry: Del offends courtly hit man Charlie (Morgan Freeman) and his excitable protege Wesley (Chris Rock), and is violently dispatched. Betty, traumatized by this savage event, enters into a fugue state that allows , even encourages, — her to keep functioning... in a kind of alternate reality. Betty Sizemore becomes "Nurse Betty," who is set on returning to the love of her life, Dr. Ravell, whom she jilted at the altar six years ago.

Betty promptly leaves Kansas in a "borrowed" 1997 Buick LeSabre, which is precisely what her late husband's killers are looking for. They, in turn, set off after Betty, but she has a head start and is intensely focused on her mission. Miles behind their quarry, the hit men formulate wildly differing assessments of their prey: Wesley sees her as a coldly calculating criminal, while Charlie begins to obsess about her. Back in Fair Oaks, Sheriff Ballard (Pruitt Taylor Vince) and local reporter Roy Ostrey (Crispin Glover) are investigating Del's murder and Betty's sudden, unexplained disappearance.