A cunning bank robber named Jack Foley (George Clooney) and a determined U.S. Marshal Karen Sisco (Jennifer Lopez) find their fates intertwined during a chaotic escape from a Florida prison. The story begins with Jack, a smooth operator who only got caught due to a dilapidated getaway car, launching a daring escape through a tunnel dug by fellow inmates.
As he makes his way out, Karen happens to be at the prison visiting her client, and she unexpectedly becomes involved in Jack's flight. Jack, seeing an opportunity, takes Karen's gun and forces her into the trunk of a car driven by a friend named Buddy. With police hot on his trail, Jack evades capture, cruising north alongside Buddy and the unreliable Glenn Michaels, another associate.
Their destination is Bloomfield Hills, a prosperous suburb of Detroit, where they plan to meet shady businessman Richard Ripley (played by Albert Brooks), who had boasted of a hidden stash of uncut diamonds worth millions. Ripley, formerly a Wall Street broker, had served time for defrauding clients and claimed to possess a treasure of $5 million in gems at his home.
Meanwhile, Karen cleverly persuades Glenn to help her escape, promising not to label him as an accessory in Jack's prison break. However, Glenn's poor driving results in an accident, leading to complications. In a surreal moment, Karen dreams of pursuing Jack but their encounter turns into an unexpected intimacy, only for her to awaken in a hospital bed, where she faces interrogation from her FBI colleague Daniel Burdon (Wendell B. Harris Jr.) about her hesitation to confront Jack.
As she delves deeper into the case, Karen learns about Jack's girlfriend Adele (Catherine Keener), who played a pivotal role in orchestrating Jack's escape. She manages to arrest another escapee, Chino (Luis Guzmán), and is reluctantly integrated into the task force meant to capture Jack and Buddy. Yet, she finds herself sidelined and assigned trivial duties.
Amidst this chaos, Glenn reveals the diamond plot to criminal Maurice Miller (Don Cheadle), who also has a history with Jack and Ripley. Together, they hatch a plan to rob Ripley’s mansion. Just when it seems Jack is out of the loop, events converge with Karen tracking Glenn to a boxing venue where the heist is set to unfold.
The tension escalates as past relationships unravel. Jack, who once protected Ripley in prison, longs for vengeance after being promised a job that turned out to be below his expectations. The story unfolds with romance, deception, and violence, leading to a dramatic confrontation at Ripley’s house.
In a series of misfortunes during the heist, mishaps ensue, leading to unexpected losses, including the life of a crew member, the revelation of Ripley hiding, and a desperate Jack realizing the threat Maurice and his team represent. Karen, also shadowing the action, ultimately takes matters into her own hands, killing Maurice and arresting Jack despite his pleading for her to "pretend [he's] someone else."
As the plot wraps up, Jack is transferred back to prison, his fate seemingly sealed. However, an intriguing twist awaits as he encounters Hejira Henry (Samuel L. Jackson), a seasoned escape artist, in the van heading back to Florida, hinting at promise and peril ahead as this unpredictable journey comes to a close.
