Lisa Reisert (Rachel McAdams) arrives at the airport to take a red-eye flight from Dallas/Fort Worth International Airport back to Miami after attending her grandmother's funeral. While waiting in the check-in line, she meets Jack Rippner (Cillian Murphy), who is boarding the same plane. After their flight is delayed due to bad weather concerns, they meet again at an airport bar and engage in small talk while they wait. When boarding, Lisa discovers to her surprise that Jackson is seated beside her.
Soon after take off, Lisa learns from Jackson that he is working for a domestic terrorist organization planning to assassinate Charles Keefe (Jack Scalia), the current United States Deputy Secretary of Homeland Security. Lisa is instrumental in their plans because of her job at the Keefes' hotel, The Lux Atlantic Hotel, as Acting Manager. Lisa must make a call from the in-flight phone to arrange for Keefe to be moved to the targeted room where a missile will be fired from an adjacent boat in a harbor, killing Keefe and his family. Jackson threatens to kill her father, Joe (Brian Cox) with a hitman should she refuse to cooperate.
Lisa attempts to find a way to keep both her father and Keefe safe. When she first places a call to the hotel, answered by her co-worker, Cynthia (Jayma Mays), the line goes dead midway through the conversation, and Lisa tries (unsuccessfully) to fool Jackson into thinking she is still ordering the room change, but Jackson catches on. She then makes two unsuccessful tries to alert the other passengers to the danger. She first attempts to write a warning in a book, when the Nice Lady (Angela Paton) from the check-in line she met and gave the book to comes to talk to her about it, but Jackson knocks her unconscious and manages to get the book back before the woman sees the message. She tries again when the airphones go out due to the storms. Lisa goes to the restroom, and writes a warning in soap on the mirror, but Jackson confronts her and sees the writing on the mirror, and forces Lisa back inside, locking the door. A little girl witnesses Jackson enter the bathroom with Lisa still inside and notifies an attendant, but she dismisses it as Jackson and Lisa having sex. When Lisa begs him not to kill her father, Jackson simply responds by telling her she should stop gambling with his life. He then notices a scar above Lisa's breast, and asks her if someone did that to her. When she tells him no, he believes that she is lying and briefly chokes her before wiping away the message.
When Lisa and Jackson return to their seats, Lisa makes the phone call, and the hotel staff move the politician to the targeted suite. After the call, she asks Jackson to call off the man outside her father's house, but he refuses until he has confirmation of the assassination.
As the plane lands, Lisa confesses that the knife scar was from a violent rape she suffered two years ago, which she swore she would never let happen again. She then stabs Jackson in the throat with a pen that she stole from another passenger, then takes his phone and flees the plane and terminal, narrowly escaping both Jackson and airport security. The little girl from before witnesses the stabbing and helps Lisa escape by pushing a suitcase into Jackson's way, causing him to fall. Once outside, Lisa steals a nearby SUV. Noticing that the phone has a low-battery warning and could die at any time, she once again calls the hotel, alerting Cynthia to the danger. Cynthia pulls the fire alarm to evacuate the building and rushes to warn Keefe and his family, who are in the targeted suite. Cynthia, the Keefes, and U.S. Secret Service agents manage to escape from the room seconds before a Javelin missile hits.
Lisa, still driving, tries to call her father, but the cell phone's battery dies. She rushes to her father's house, arriving to find the hitman outside his door. He pulls out a gun and shoots through the windshield numerous times, attempting to kill her, but fails when she hits him with the car and sends him propelling into the house's front door, killing him. Lisa finds her father inside, and he tells her that he has called the police because of the car crash. While Lisa phones the hotel to check that everyone is all right, Jackson arrives and knocks her father unconscious. He chases her through the house with a knife and they fight until Jackson manages to throw Lisa down a flight of stairs. Lisa retrieves the dead hitman's gun from the floor and threatens Jackson with it. He attempts to escape, but Lisa shoots him before he can. He disarms and attacks her and is about to kill her when Lisa's father takes a gun and shoots Jackson in the chest, believed to be fatally.
Later at the hotel, Keefe and the Secret Service thank Lisa and Cynthia for saving him and his family from the assassination. Bob and Marianne Taylor, two of the visitors at the hotel confront Lisa and Cynthia and angrily complain about their stay. Lisa tells them to fill out a comment card at the front desk, and then tells them to shove it up their ass.
Who does Jackson threaten to kill if Lisa does not cooperate?
Her father