Betty Sizemore (RENEE ZELLWEGER) is a small town waitress in Fair Oaks, Kansas who gave up on her dreams of becoming a nurse due to her abusive, car salesman husband, Del (AARON ECKHART), who treats her like dirt, even on her birthday. Consequently, she lives vicariously through her favorite soap opera, "A Reason To Love," a TV melodrama set in a hospital, and is enamored with the character of Dr. David Ravell, played by actor George McCord (GREG KINNEAR).
When Betty witnesses two hit men, Charlie (MORGAN FREEMAN) and Wesley (CHRIS ROCK), murder Del during a "business" arrangement gone bad, she mentally snaps. As a result, she imagines herself as and then literally becomes Nurse Betty, a woman who jilted Dr. Ravell at the altar several years earlier but now wants to rekindle that love.
As such, she leaves her Kansas town headed toward Los Angeles and the fictitious TV hospital that she believes exists in Los Angeles, with Charlie and Wesley a day or so behind her, hoping to recover the stolen goods she doesn't realize are in the trunk of her car.
While Sheriff Ballard (PRUITT TAYLOR VINCE) and Fair Oaks reporter Roy (CRISPIN GLOVER) try to figure out Betty's disappearance and her involvement in Del's murder, the deranged woman arrives in Los Angles. There, she's befriended by Rosa (TIA TEXADA), a law firm employee who houses and helps her locate McCord.
Upon hearing Betty's elaborate story about her and Dr. Ravel, McCord and the show's producer, Lyla (ALLISON JANNEY), think she's an aspiring actress doing a creative pitch. As they soon get to know her, however, and as the two hit men close in on her, it's only a matter of time before everyone figures out who she really is as everything comes to a cumulative head.