In a small Kansas town, Betty (Ren e Zellweger), a kind and considerate diner waitress, is a fan of the soap opera A Reason to Love. She has no idea that her husband, Del (Aaron Eckhart), a car salesman, is having an affair with his secretary and that he intends to leave Betty to pursue a relationship with her. She also doesn't know that her husband supplements his income by selling drugs out of the car dealership. When Betty calls to leave a message about borrowing a Buick LeSabre for her birthday, her husband tells her to take a different car, as the LeSabre (unknown to Betty) has stolen drugs hidden in the trunk.
Two hitmen, Charlie and Wesley (Morgan Freeman and Chris Rock), show up at the house with Betty's husband. The hitmen torture Betty's husband into revealing that he has hidden the drugs in the trunk of a car, but Wesley scalps him anyway. Betty witnesses the murder and experiences a fugue state, escaping the reality of murder into the comforting fantasy of the soap opera. In her mind, she assumes the identity of one of the characters in the daytime drama, a nurse.
That evening, Sheriff Eldon Ballard (Pruitt Taylor Vince), local reporter Roy Ostery (Crispin Glover), and several policemen examine the crime scene while Betty calmly packs a suitcase. She seems oblivious to the murder, even with the investigation going on right in her house. At the police station, a psychiatrist examines her. Betty spends the night at her friend's house, sleeping in a child's bedroom with the innocence of a little girl. In the middle of the night, she gets into her car and drives off. Betty's next stop is a bar in Arizona, where the lady bartender talks about her inspiring vacation in Rome, and Betty tells her that she was once engaged to a famous surgeon (describing the lead character from A Reason to Love   not the actor who portrays him).
Meanwhile, the two hitmen are trying to find her, as they have finally realized that she must have the car with the drugs. As they search, Charlie begins falling in love with his image of Betty, to Wesley's consternation. In Los Angeles, Betty tries to get a job as a nurse while looking for her long-lost "ex-fianc ". She is turned down due to having "forgotten" her r sum  and references but manages to get a job in the pharmacy due to her help in saving the life of the victim of a drive-by shooting.
Despite an injunction against touching any patients, Betty becomes popular with them and their families. She ends up living with Rosa (Tia Texada), a Hispanic legal secretary who has had a series of painful love affairs and offers to help Betty find her surgeon boyfriend. Rosa learns from a colleague that "David" is just a soap opera character, and she goes to the pharmacy window to confront her. Betty thinks her friend is jealous and is impervious to the revelation.
The lawyer has an idea and supplies tickets to a charity function where George McCord (Greg Kinnear), the actor portraying David, will be appearing. Betty meets George at the function. George is inclined to dismiss her as an overimaginative fan, but something about her compels him to walk back and talk to her some more. He begins to think that Betty is an actress determined to get a part in the soap opera, so he decides to play along. After three hours of her "staying in character", he takes her home.
George begins falling in love with her, and he and his producer decide to bring her onto the show as a new character: Nurse Betty. When Betty arrives on set, she falls out of her fantasy world back into real life, as seeing the inner workings of a television show snaps her back into reality. After two failed takes, she realizes that she is on a set and that the people she thought were real are just characters portrayed by actors. George confronts her for being a "crazy person", and Betty walks out.
Now recovered, Betty begins to tell Rosa what happened when the two hitmen come into the house to decide what to do with them after they find the car with the drugs outside Rosa's house. The killers are interrupted by the reporter and Sheriff Ballard from Betty's hometown who have also tracked her down. A standoff ensues in which Ballard pulls out a gun from an ankle holster and shoots and kills Wesley, who is distracted by watching a taped airing of A Reason to Love. At this point, Wesley is revealed to be Charlie's son. Charlie, rather than be arrested, decides not to kill Betty and commits suicide in the bathroom.
George offers Betty a job on the show. She appears in 63 episodes and takes a vacation in Rome. Betty later plans to pursue nursing as a career.
Output: What happens after Betty attends a charity event?