Ryan Weaver, [Ray Liotta], an accused serial killer and rapist, is arrested in New York City despite his claims of innocence. Even though police lieutenant Aldo Hines, [Héctor Elizondo], broke protocol during the arrest by assaulting Weaver, the authorities have enough hard evidence to extradite him to Los Angeles to face trial. Weaver and another prisoner, a bank robber named Stubbs, [Brendan Gleeson], are escorted by four U.S. marshals onto a TransContinental Airlines 747. Even though it is Christmas Eve, the 747 is nearly empty, with only eleven people on board.
During the flight, Stubbs breaks free while using the bathroom and begins a shootout with the marshals. A stray bullet punches a hole in the fuselage, causing explosive decompression, before the hole is sealed with a briefcase. Amidst the chaos, the captain, Captain Samuel Bowen, [Ben Cross], is fatally shot and the first officer is knocked out when his head slams into the yoke, disengaging the autopilot in the process. Weaver frees himself and attempts to save the last remaining marshal, but fails when Stubbs shoots him dead after being shot himself. Weaver enters the cockpit and finds the co-pilot unconscious but breathing.
Weaver appears to be horrified by the ordeal, increasing the passengers' trust in him. With the flight crew lost, Teri Halloran, [Lauren Holly], a flight attendant, makes her way into the cockpit and learns she is the only one left capable of keeping the 747 from crashing. The co-pilot is heavily implied to have been murdered by Weaver off-screen. To make matters worse, the plane is heading into a storm which threatens severe turbulence.
Weaver's behavior becomes increasingly erratic and paranoid, suffering nervous breakdowns. He locks the passengers in the crew's cabin, then attacks and strangles Maggie, one of the other flight attendants, to death. Weaver then calls Hines at the FBI control center at LAX and threatens to crash the 747 into their facility, stating that he is willing to do anything to avoid being arrested. Weaver reveals to Teri that he committed the murders and attacks her, but she manages to trap him below deck.
After the plane survives severe turbulence, Teri must be instructed by radio on how to reprogram the autopilot to land at LAX. Her task is complicated by Weaver's obscene and constant interruptions. Weaver breaks into the avionics bay and smashes the server running the primary autopilot software, rendering the first landing attempt unsuccessful, and forcing a last second go-around. The plane skims a rooftop Japanese restaurant and a multi-story parking garage, but regains the air, though the landing gear picks up a Ford Ranger pickup. The backup autopilot engages, allowing Teri to make efforts to turn the plane around. However, an Air Force officer at LAX sends an F-14 Tomcat to intercept the 747.
Teri begs the authorities not to have her shot down, insisting she can land the plane. Weaver breaks into the cockpit with an axe and tries to kill her, but the F-14 destroys the truck instead, shaking the 747 and giving Teri a chance to attack. Teri retrieves a .38 revolver and, in the midst of Weaver's assault, manages to load a bullet and shoots Weaver through the head, killing him. She returns to the pilot's seat and, with radio assistance, safely lands the 747 using the autopilot. Despite Weaver's claims that he killed them all, the other crew and passengers are found alive.
