Justine Last (Jennifer Aniston) is a depressed 30-year-old woman living in a small town in Texas with her husband Phil (John C. Reilly), a house painter who spends most of his free time smoking marijuana with his best friend, Bubba (Tim Blake Nelson). Justine works at Retail Rodeo, the local big-box store, along with Cheryl (Zooey Deschanel), a cynical, plain-spoken young woman, Gwen (Deborah Rush), a ditzy older woman who manages the cosmetics counter, and Corny (Mike White), a security guard.
One morning, Justine notices a new cashier, Holden (Jake Gyllenhaal) and later introduces herself. Holden, similar to Justine, is shy and reserved which helps the two quickly bond. They begin spending time together and Justine tells Holden how she feels underappreciated by Phil and Holden tells her about his obsession with J. D. Salinger’s novel, The Catcher in the Rye, and how he took his self-assigned first name from its protagonist, Holden Caulfield.
As the weeks go by, Justine and Holden bring out the best in each other. But when Holden makes a pass at her, she rejects him, leaving him dismayed. He becomes more and more besotted by her. Sometime later, Holden does not show up to work but sends a letter to Justine, writing that if she does not meet him at 5pm that day behind the nearest Chuck E. Cheese, she will never see him again. After much consideration, Justine decides to accept Holden’s invitation, only to be intercepted by her manager, Jack (John Carroll Lynch), who insists that she take a very ill Gwen to the hospital. Justine then meets up with Holden. The two have sex for the first time in a motel room.
As the affair continues, Justine’s marriage to Phil continues to deteriorate. One night, Justine spots Bubba’s truck in the parking lot of the motel where she’s been meeting Holden. She becomes convinced that Bubba knows, telling Holden that they need to stop for a while. When Justine goes to visit Gwen in the hospital, she is told that Gwen has died after contracting parasites from eating poisonous blackberries that she bought at a roadside fruit stand. When she returns home, Bubba starts hinting to Justine that he knows about her affair with Holden. Feeling guilty, Justine suggests that she and Phil should attend a church bible study that Corny, the security guard, had invited them to. Soon after they arrive, Justine spots the motel desk clerk she encountered with Holden. She grabs Phil and demands they leave immediately.