Faced with a precarious situation at work stemming from his drinking habits, Osbourne Cox (John Malkovich) reacts to his impending demotion by resigning from his position as a CIA analyst. Determined to document his life experiences, he sets off to write a memoir. However, his plans are derailed when his wife, Katie (Tilda Swinton), seizes this moment to initiate divorce proceedings while continuing her extramarital affair. Acting on her attorney's advice, she discreetly copies sensitive financial records and a convoluted diatribe from Osbourne’s computer onto a CD. Unbeknownst to her, this CD holds chaotic thoughts about CIA operations.
The CD, which gets accidentally left in the locker room of Hardbodies, a local gym, is discovered by the clueless personal trainer Chad Feldheimer (Brad Pitt) and his colleague Linda Litzke (Frances McDormand). They mistakenly interpret the seemingly innocuous bank details and Osbourne’s rants as vital government intelligence. Believing they are onto something significant, they plot to return the CD to Osbourne in exchange for a reward, with Linda aiming to finance her desired cosmetic surgery.
Unfortunately, their plan spirals out of control following a tense encounter with Osbourne, leading them to offer the disc to the Russian embassy for monetary gain. With no other leads, Linda convinces Chad to break into the Cox home to extract additional information from Osbourne’s computer. In the meantime, Osbourne's increasingly erratic behavior, partly fueled by the chaos surrounding him, prompts Katie to push forward with the divorce, even changing the locks on their home, forcing Osbourne to take refuge on their sailboat docked in the Chesapeake Bay.
With Osbourne out of the picture, Katie invites Harry Pfarrer (George Clooney), a charming but unfaithful U.S. Marshal who is also entangled with Linda, to live with her. In a twist of fate, Harry encounters Chad hiding in the Cox residence, resulting in a panicked confrontation where Harry fatally shoots Chad.
Days later, at CIA headquarters, Palmer Smith ([David Rasche]), Osbourne’s former superior, finds himself embroiled in a bizarre situation where they discover that Osbourne’s information has ended up with the Russian Embassy, leaving them puzzled over the motives behind this unprecedented breach of protocol. Desperation mounts as Harry gets into a heated argument with Katie and leaves, only to be pursued by a private investigator hired by his wife Sandra (Elizabeth Marvel) to gather evidence for her own divorce.
As Harry grapples with the fallout of the shooting and begins to suspect Linda of being a spy, she, in turn, seeks help from Ted Treffon ([Richard Jenkins]), the kind-hearted gym manager who harbors feelings for her. Convinced that Chad has been abducted by the Russians, Ted agrees to search for more information at the Cox residence. Meanwhile, Osbourne, now desperate and without funds, breaks into his own home only to mistakenly kill Ted, thinking he is Katie’s new lover.
Ultimately, events spiral further out of control; the CIA catches up with Linda and Harry while a bullet has left Osbourne in a coma following his violent confrontation with Ted. The CIA debates whether to allow Harry to flee to Venezuela, as he is caught in an increasingly convoluted web of misunderstandings and poor choices. In a cynical conclusion, the CIA reviews the debacle, realizing that despite the chaos, they have learned nothing but painful lessons about their own incompetence. Meanwhile, at the Russian embassy, the trivial contents of Osbourne's ramblings are dismissed as "drivel," closing the loop on this darkly comedic tale of errors and misjudgments.
