Faced with a demotion at work because of an alleged drinking problem, Osbourne "Ozzie" Cox angrily quits his job as a CIA analyst and decides to write a memoir. When his pediatrician wife Katie finds out, she sees it as an opportunity to file for divorce and to continue her affair with Harry Pfarrer, a married U.S. Marshal with paranoid tendencies. At the instruction of her lawyer, Katie copies and delivers her husband's digital financial records and other files, unknowingly including the draft of Ozzie's memoir. The lawyer's assistant copies the files onto a CD, which she accidentally leaves on the locker room floor of Hardbodies, a local gym. The disc falls into the hands of dimwitted personal trainer Chad Feldheimer and his coworker Linda Litzke, who mistakenly believe it to contain sensitive government information.
Chad devises a plan to return the disc to Ozzie for a cash reward, with Linda eager to raise money for cosmetic surgery that she cannot afford. After a phone call and subsequent meeting with Osbourne provoke his furious reaction, Chad and Linda try to sell the disc to the Russian embassy, and they meet with an official there who is actually a spy for the CIA.
Osbourne's increasingly temperamental and erratic behavior prompts Katie to change the locks on their house and to invite Harry to move in. Harry is a womanizer and routinely dates and sleeps with women whom he has met online. He coincidentally starts seeing Linda after meeting her on a dating site.
Having promised the Russians more files, Linda persuades Chad to sneak into the Cox house to steal files from Ozzie's computer. After watching Katie and Harry leave the house, Chad enters and starts snooping around until Harry unexpectedly comes home. Chad rushes upstairs to hide in the bedroom closet as Harry enters the room and takes a shower. After Harry has dressed, he picks up his gun and opens the closet to retrieve his holster. Startled at seeing Chad, he shoots Chad in the head, instantly killing him. Harry searches the body for any clues to Chad's identity, but only finds an empty wallet. He suspects that Chad was a spy who had been snooping on him.
Two days later at CIA headquarters, Palmer Smith, Osbourne's former superior, and Smith's director learn that information from Osbourne has been given to the Russian embassy. They are perplexed because the information is of no importance and the perpetrators' motive is unknown. Smith also discloses to the director that the agent whom they had assigned to spy on Harry observed Harry dumping Chad's body into Chesapeake Bay. The director, unaware of Chad's identity, orders Chad's death to be covered up.
Harry and Katie have an argument and Harry storms out of the house when he spots a man who has been trailing him for the past several days. Harry tackles the man and the man admits that he is working for Tuchman Marsh,[9] a law firm that Harry's wife Sandy has retained in order to divorce Harry. Harry is devastated at the surprise revelation of Sandy's divorce plans and goes to see Linda to vent his despair. However, Linda complains to Harry that she cannot always be the one to listen to everyone's problems and confides that she has her own issues because Chad is missing. Harry agrees to help find Chad, unaware that Chad is the man whom he had shot and killed.
Linda returns to the embassy, believing that the Russians have abducted Chad, but they deny that they have him. They dismiss the CD contents as "drivel" and escort Linda out of the embassy. She turns to Ted Treffon, the kindhearted manager of Hardbodies who has unrequited feelings for her, and begs him to help her by sneaking into the Cox household to gather more files from Osbourne's computer.
Harry and Linda meet in a park. Harry notices a man in the park who appears to be surveilling him. Linda recognizes him as a man whom she had previously dated but denies knowing him, furthering Harry's suspicions. When Linda reveals the address where Chad had gone before disappearing, Harry realizes that Chad is the man whom he had shot. Convinced that Linda is a spy and that everyone in the park is surveilling him, he panics and flees.
Osbourne becomes unhinged when he finds out that Katie has emptied his bank accounts and breaks into the house to retrieve his alcohol and personal belongings. Finding Ted in the basement, Osbourne shoots him and chases him onto the street, where he attacks him with a hatchet.
At CIA headquarters a few days later, Smith tells the director that a surveilling CIA agent intervened in the fracas between Osbourne and Ted, shooting Osbourne and leaving him in a coma, and that Ted died from the attack. He also says that Harry has been detained while trying to flee to Venezuela, a country with no extradition treaty with the U.S. The director instructs Palmer to let Harry continue on to Venezuela rather than deal with the consequences of bringing him into custody. The director and Palmer agree only to worry about dealing with Osbourne if he wakes. Linda promises to keep quiet if they will pay for her plastic surgery, to which the director agrees.
Palmer and his director try to make sense of all the events. They conclude that no lesson can be learned for the agency. "I guess we learned not to do it again," the director says, despite not knowing exactly what was done, and closes the file.
George Clooney as Harry Pfarrer
Frances McDormand as Linda Litzke
Brad Pitt as Chad Feldheimer
John Malkovich as Osbourne Cox
Tilda Swinton as Katie Cox
Richard Jenkins as Ted
Elizabeth Marvel as Sandy Pfarrer
David Rasche as CIA Officer Palmer DeBakey Smith
J. K. Simmons as CIA superior
Olek Krupa as Krapotkin