The movie begins in an Eastern Orthodox church in Pale, Bosnia and Herzegovina, when an unidentified man (later revealed to be a Bosnian diplomat to the UN) is murdered in an alley after receiving a page to meet someone outside.
The scene then immediately shifts to a missile base in Chelyabinsk, Russia, where SS-18 ICBM's are being decommissioned. Ten nuclear warheads are loaded onto a train and sent to a separate site for dismantling. However, a high-ranking Russian general, Aleksander Kodoroff, has other plans. Along with a rogue tactical unit, he kills all the soldiers onboard the train and then transfers nine of the warheads to another train. He also sets the timer on the one remaining warhead, then switches tracks to send his train out of harm's way and the transport train on a collision course with a passenger train. Inside a mountain tunnel, Kodoroff kills one of his high-ranking lieutenants who'd had reservations about the mission. A few minutes later the trains collide. The thermonuclear warhead goes off moments later, yielding a blast about 500 kilotons in intensity. The explosion immediately garners the attention of the US government.
Even though the detonation was staged to look like an accident, White House nuclear expert Dr. Julia Kelly (Kidman) is not convinced: SS-18 warheads can only be detonated deliberately. She believes that terrorists are behind the incident. Her newly assigned military liaison disagrees with her. He is smooth-talking and irreverent US Army Special Forces officer Lieutenant Colonel Thomas Devoe (Clooney), and he is convinced that the crash and the detonation were both staged, to hide the hijacking of the other warheads on board. A call to Devoe's long time friend and Russian counterpart, Dmitri Vertekoff (Armin Mueller-Stahl), adds credence to his hypothesis.
Kelly and Devoe try to track down the terrorists through an Austrian trucking company which is a front for the Russian Mafia. Devoe and Kelly go to the company's offices and, when Kelly is unable to get answers, Devoe resorts to more drastic measures, beating the man, tying him up and threatening to shoot him in the knee. Kelly is able to retrieve vital invoices from the man's computer and the two leave the building.
When the Mafia realizes they are in fact U.S. government agents, they send out several carloads of thugs to kill them. Vertekoff is killed, but Kelly and Devoe escape, with Devoe killing most of the would-be assassins in the process. Though the paper invoices Kelly retrieved are destroyed when Devoe ignites the gas tanks of his & the thugs' car, Kelly is able to download them from her email. When they're examined, Devoe recognizes Kodoroff's name. Kodoroff is known to be fanatical and Devoe assumes that the rogue general will sell the warheads to a country linked to terrorism.
Devoe later finds out through the tracking system of the truck company that the nukes are in a truck headed to Iran by way of Dagestan. Kodoroff and his crew are located using a ruse in which Devoe convinces the driver over the phone that there is a smart bomb falling towards him, causing him to turn out of traffic on a road, so that the truck can be seen in an aerial photo. After the only Russian troops in the area are killed by the general and his men, one of the crew takes one of the warheads and leaps off the truck, hiding in the forest nearby.
Devoe leads a group of USAF Special Operations and Army Rangers illegally over the Russian border to seize it. During the operation, one of their choppers is shot down by Russian SAM battery when they enter Russian airspace, but the remaining choppers evade the missiles and are able to stop the truck carrying the warheads. A savage fight ensues onboard the vehicle, and Kodoroff is killed and the warheads are seized. Interrogation of the one surviving member of the group reveals that the trigger bomb (nominal yield: 1-2 kilotons) from one of the warheads is missing. It is learned that the bomb was taken by a Bosnian Serb, and that it may be intended to destroy the UN headquarters in New York. The man who stole the warhead is the brother of another of the terrorists, Duan Gavri (Marcel Iure), is a Yugoslav without identity ("I am a Serb, a Croat, and a Muslim" in reference to all sides in the war torn former Yugoslavia). He wants to avenge the death of his wife and daughter, who were killed by a sniper in Sniper Alley, Sarajevo. He blames the countries of the West for not protecting them and for greedily supplying weapons to all sides in the war. He therefore plans to blow up the United Nations building in New York City, and supplies a videotaped message warning the governments of the west to cease their involvement in the Yugoslavian conflict.
Gavri is finally tracked down in Manhattan, wounded, and cornered into a Catholic church near the UN. Davoe confronts Gavri, saying, "It's not our war!" Gavri responds, "It is now!", and promptly commits suicide, knowing that the bomb is set to go off in a matter of minutes, and cannot be deactivated. With seconds to spare, Kelly is able to remove a part of the bomb's explosive lens shell, preventing it from creating a critical mass within the plutonium core. The remaining explosives go off, but the bomb does not detonate and the explosion is confined to the church. Devoe and Kelly both survive the explosion with minor injuries.