Traumatized as a result of witnessing her husband’s brutal slaying, Betty (Renee Zellweger), a small-town waitress and soap opera fan, enters a fugue state that allows — even encourages — her to keep functioning… in a state of alternate reality. Now living out the fantasy life of the erstwhile Nurse Betty, she is set on returing to the love of her life, the lead character on Betty’s favorite medical soap opera… the fictional Dr. Ravell.

Betty promptly leaves town in the car that her late husband’s killers are looking for. They, in turn, set off after Betty, followed also by the local sheriff Ballard (Pruitt Taylor Vince) and local reporter Roy Ostrey (Crispin Glover), who are investigating her husband’s murder and Betty’s sudden, unexplained disappearance. When she finally tracks down her (fictional) love interest, the actor that plays him, George McCord (Greg Kinnear) isn’t sure what to make of her. With the hit-men hot on her trail, life begins to imitate art… and vice versa.