After attending her grandmother's funeral in Dallas, Texas, Lisa Reisert (Rachel McAdams), who has a fear of flying, takes a red-eye flight to Miami, Florida.
While in the check-in line she meets an older lady (Angela Paton) who is interested in Lisa's Dr. Phil book. She tells her she's a fan, so Lisa gives the woman her book saying she has already read it.
Lisa also meets Jackson Rippner (Cillian Murphy), a man whom she initially finds charming. After their flight is delayed due to weather, Lisa meets with Jackson again in the bar and they talk to each other while having a drink. When boarding, Lisa is pleasantly surprised to find that Jackson is seated beside her. She's even more impressed when Rippner calms down a rude passenger (Loren Lester) who was giving a hard time to the airline attendant (Mary-Kathleen Gordon).
After take off, Lisa is shocked when Jackson transitions into something she never expected, revealing to her that he is a terrorist operative working for a group who intends to assassinate the United States Deputy Secretary of Homeland Security Charles Keefe (Jack Scalia) and his family. He tells Lisa that she is instrumental in their plans because of her job as Acting Manager at the Lux Atlantic Hotel where the Keefe family will be staying. If she refuses to cooperate, Rippner will deploy a hit man to kill her father, Joe (Brian Cox) at his home in Miami.
Lisa's task is to use the in-flight phone to call her assistant at the hotel and tell her to change the room that the Keefe's will be staying in, even though they always stay in the same room and any room they use has to be pre-cleared by the Secret Service. Lisa tries to convince Rippner that she doesn't have that authority, but he knows better and orders her to make the call and order the hotel staff to change the reservation from the inner room 3825 to suite 4080, which faces the harbor.
When Lisa 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 Rippner into thinking she is ordering the room change as directed, but then Rippner notices a nearby passenger trying to make a call and looking with frustration at his phone. There's a message on the screen on the back of the phone which says "service temporarily unavailable." Rippner grabs the phone away from Lisa and confirms it's dead. He's not happy.
Lisa attempts to find a way to keep both her father and Keefe safe. Her first attempt is when the older lady from the check-in line comes to talk to her about the Dr. Phil book (Rippner had been asked by the flight attendant to help with positioning some luggage in the overhead). The woman asks Lisa to write some things in the book. Lisa tries to write a warning in the book, but Rippner is ever vigilant and realizes what she was doing. When he returns to his seat, he head butts her unconscious and puts a pillow under her head to make it appear she is simply sleeping. He then manages to steal the book back from the older woman before she is able to see the message.
Lisa tries again by going into the restroom and writing a warning on the mirror with hand soap, that there's a bomb where Rippner is sitting. As she opens the door to leave the restroom, Rippner is standing there. He sees the message on the mirror and pushes Lisa back into the restroom and shuts the door. He slams her around and chokes her, then wipes the message off. He warns her again not to gamble with her father's life. Rippner notices a scar above Lisa's breast and asks her about that, but she refuses to answer.
A small girl who was waiting to use the restroom tells the flight attendant that two people were in the restroom. The flight attendant assumes the couple are in the process of becoming members of the Mile High Club, so she doesn't intervene, but the little girl is savvy enough to realize that things aren't that way between the man and woman in the restroom. Nevertheless, she remains quiet about it during the rest of the flight.
When Lisa and Jackson return to their seats, Lisa makes the phone call to Cynthia, and Cynthia meets the Keefes and their Secret Service escorts in the lobby and informs them of the need to change the room due to a plumbing problem. When Keefe learns it was Lisa who ordered the change, he tells the Secret Service to go ahead and clear the new room.
Lisa wants Rippner to call his hit man and order him to stand down, now that she'd done her part, but Rippner says he still needs her, as he can't let her and her father go until he gets a phone call confirming that Keefe has been successfully dealt with. When she expresses concern that the hit man might get impatient and act before being called off, Jackson reassures her that he'll only act on Jackson's orders, saying that "he's a good dog, who only responds to the sound of his master's voice." Lisa soon realizes that not only Keefe to be killed, but his family too, and she's even more distressed.
The Secret Service do a thorough sweep of the new room and even contact the Coast Guard to go investigate a fishing boat sitting way out in the harbor. When the Coast Guard boards and inspects the boat, they call in that it's all clear. The hotel staff then move Keefe and his family into the new suite.
As the plane is landing in Miami, Lisa confides in Rippner, telling him that the scar on her throat was from a knife held to her throat by a rapist two years ago. When Rippner observes that there was nothing she could do about it, she disagrees and tells him she swore that she would never let it happen again. She then jerks her right hand and arm up and around and stabs Rippner in the throat with an ink pen she stole earlier from a young male passenger.
The pen punctures Rippner's windpipe and damages his vocal chords. Lisa climbs over him and as she goes by, she takes his phone and scrambles to make her way through the aisle and other passengers to the main exit door. A young male passenger who'd been falsely accused by his friend of taking his ink pen, wryly observes that now they know what happened to his pen.
Lisa has to wait until the door is open, giving time for Rippner to gather himself, pull the pen from his throat, wrap a scarf around his neck, and start after her. Rippner is slowed a bit more when the little girl who'd been observing him during the flight shoves her little carryon bag out into the aisle, tripping him and knocking him down.
The men on that fishing boat that had been cleared by the Coast Guard, are shown hauling in a fishing line. On the other end of the line is a large container which they load onboard and open, revealing the component parts to an FGM-148 Javelin man-portable fire-and-forget anti-tank missile. They begin assembling the weapon.
Lisa flees the plane, removing her thin sweater and tossing it into the trash, as security had already been alerted. She narrowly escapes Rippner and airport security. Once outside, she steals an SUV from a driver who was greeting an arriving passenger.
Lisa makes a call with Rippner's phone, noting that it has a low-battery warning, so she's worried about that. However, she is able to get through to Cynthia at the hotel, telling her what's going on, then ordering her to pull the fire alarm and make sure to get the Keefe's out of their suite immediately. Cynthia is freaking out, but she does exactly what Lisa told her to do.
The Secret Service get the Secretary and his family out of the room just seconds before the Javelin missile is fired. It races across the sky and plows into the suite, exploding and destroying the room and everything in the immediate vicinity. Cynthia, the Keefes and the Secret Service agents all managed to escape the room seconds before. The men on the fishing boat toss their weapon overboard and take off.
Lisa, still driving, tries to call her father, but the cell phone's battery dies just as he picks up the phone and says hello. She rushes to her father's house, arriving to find the hit man (Dane Farwell) standing just outside the front door. He hears Lisa approach and turns to face her, reaching inside his jacket. Lisa turns the SUV and floors the accelerator, jumping the curb and slamming into the hit man, driving him through the front door, killing him.
Lisa finds her father inside. He is shocked not only by a vehicle slamming into his front door, but seeing a man lying on the entryway and then his daughter walking in. He tells Lisa that he has already called 911.
Lisa calls the hotel to check on things there. Cynthia confirms the Keefes are ok. When Lisa turns around after talking with Cynthia, Rippner is standing there. He'd knocked out her father, Joe, who was lying on the kitchen floor. Lisa hurried to the kitchen to make sure her father was alive, then she turns her attention to Rippner. She's really angry now, telling him that he'd failed at his mission and assuring him that he's not about to defeat her in her own house.
Over the course of the next few minutes, she has the upper hand, as she throws things, punches and kicks him as he chases her through the house. He eventually returns to the body of the hit man and grabs the 12" K-Bar knife the man was going to kill Joe with.
Lisa manages to make another phone call to 911 as she sneaks around trying to figure out where Rippner had disappeared to. As she closes a bedroom door, intending to lock herself in, he is standing right there. They fight some more and she clubs him with a stout cane she'd found in the closet, knocking the knife away. He ends up throwing her down a flight of stairs. Lisa crawls down the last few steps, where she sees a gun lying next to the dead hit man. She grabs the gun and turns to threaten Jackson with it. He moves towards her anyway and she shoots him, wounding him. He kicks the gun out of her hand and grabs her by the hair. He's about to kill her when Joe appears and shouts, "hey!" As Rippner pauses and looks up, Joe shoots him in the chest.
Lisa returns to the hotel where she greets and hugs a very frazzled Cynthia. Cynthia observes that she thought things went pretty well overall during Lisa's absence, other than the most recent event. The Homeland Secretary expresses his gratitude to Lisa and Cynthia before he's ushered off.
An older man and woman, who'd been guests at the hotel that day, come up to Lisa and Cynthia, complaining about their terrible stay, with all the inconvenience and discomfort associated with the attempted assassination, wanting to know what Lisa was going to do about it. When Lisa asks them what they think should be done, they say first they wanted Cynthia fired. Lisa thinks for a moment, then suggests to the couple that they fill out a comment card. They are aghast at that, but then they are totally speechless when Lisa tells them that after they are done with that, to just go ahead and "shove it up your ass."
The movie ends with Lisa taking Cynthia out for a drink; 'anything but a bay breeze,' the kind of drink Lisa had mentioned drinking, to Jackson.