Cameron Poe (Cage), an honorably discharged United States Army Ranger is paroled after serving eight years for killing a drunken man in a bar brawl while defending his wife Tricia (Potter), pregnant with his unborn daughter Casey. While still under the penal system until his release in Alabama, Poe is to be flown back on the "Jailbird", a C-123 airplane, along with several other prisoners that are being transferred to a new Supermax prison. Drug Enforcement Administration agent Duncan Malloy (Meaney) approaches the U.S. Marshal in charge of the transfer, Vince Larkin (Cusack), and requests he slip undercover agent Willie Sims on board to coax information out of the drug lord Fransico Cindino (Borrego) during the flight before his incarceration. Larkin reluctantly agrees, but Malloy manages to slip a gun to Sims before boarding.
Shortly after the flight, the prisoners launch a choreographed effort led by Cyrus "The Virus" Grissom (Malkovich) and overcome the guards, taking control of the plane; when Sims tried to take control of the situation, he is quickly killed. Poe opts to keep his identity quiet and cooperates with Grissom, who promises all the prisoners that they will also be flown to a non-extradition country thanks to Cindino if they help out. The plane lands in Carson City as scheduled to make prisoner transfers; Grissom and his crew pose as the guards and take advantage of a dust storm to make sure the transfer appears to go smoothly, while Joe "Pinball" Parker (Chappelle) sneaks the "Jailbird"'s transponder onto a private jet. Although Poe secretly manages to get word out on the hijacking, it is too late to stop the plane from taking off. Malloy orders attack helicopters to follow the transponder, unaware it is no longer on the plane. Poe discovers that Parker did not make it back to the plane on time, his body still stuck in the landing wheel wells, and writes a message to Larkin to inform him that the plane is headed for Lerner Airfield, then dumps the body overboard onto a populated city. Larkin learns of the message, and recognizes that Poe is his ally on the plane, and calls in the National Guard while he travels alone to Lerner Airfield.
At Lerner, the plane lands but overshoots the runway, running aground. When neither Grissom or Cindino can find the promised plane waiting for them, Grissom orders the prisoners to start digging the "Jailbird" free. Larkin, sneaking about the airfield, discovers Cindino has snuck off to meet with his men at a small private jet, and quietly disables the jet before it can take off. Grissom discovers Cindino's treachery, and kills him and destroys his plane, the explosion sending a signal to the approaching National Guard. The prisoners quickly prepare to ambush the troops. Poe and Larkin happen upon each other, and quickly apprise each other of the situation, though Poe remains untrusting of Larkin's abilities. Poe returns to the plane with needed insulin shots for his fellow prisonmate, Mike "Baby-O" O'Dell (Williamson), while Larkin helps to avoid the National Guard from getting slaughtered by providing a make-shift bulletproof shield using a steamshovel. Grissom orders the remaining prisoners to retreat to the plane, and gets it in flight before Poe has a chance of getting off the plane with O'Dell. Malloy and his helicopters arrive, threatening to shoot the plane down, but Larkin orders him not to, and explains about Poe. Meanwhile, Poe's true identity is discovered, and Grissom prepares to kill him, but they find the plane has run out of fuel, and the prisoners are forced to make a landing along the Las Vegas Strip.
The landing harms or kills many of the remaining prisoners while causing massive destruction along the Strip. After the landing, Grissom, Jones, and Swamp Thing escape on a firetruck amid the chaos of destruction; both Poe and Larkin spot the escapees and follow them on motorcycles. Poe and Larkin work together to kill the prisoners, and Poe expresses his full trust in Larkin as they return. Poe is shortly reunited with Tricia and sees his daughter Casey for the first time. The last scene shows Garland Greene (Buscemi), the only prisoner to escape, playing craps and sipping whisky.
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