In a rail yard within the northern Pennsylvania town of Fuller, a pair of hostlers working for the Allegheny and West Virginia Railroad (AWVR) are ordered to move a freight train off its current track to make way for an excursion train carrying schoolchildren. One of the hostlers, Dewey (Ethan Suplee), chooses not to connect the locomotive's air hose to save time; he does this knowing that the train's air brakes will only apply on the lead locomotive in this configuration, but decides to connect the hoses after parking the train on another track. Dewey sets the locomotive's throttle at 100% in order to enable the train's dynamic brakes, but sees that an approaching switch is not set to the right track. Dewey jumps down to line the switch properly, while the dynamic brake lever in the cab, unattended, falls of its own accord. The train picks up speed, and Dewey is unsuccessful in his attempts to reboard. It leaves the yard and enters the main line unmanned.
Meanwhile, Will Colson (Chris Pine), a newly-hired conductor for AWVR, is partnered with veteran engineer Frank Barnes (Denzel Washington). Barnes and Colson meet by their locomotive for the day in the southern Pennsylvania city of Stanton, where Barnes, a 28-year employee, finds out that Colson, who will be in charge of the train, is only four months out of training. He reminds Colson that if there's anything he doesn't know, he should just ask. They take the locomotive out to where they will attach their train for the day, where, after Colson makes the mistake of picking up too many cars, they leave Stanton bound for a zinc plant.
In Fuller, the hostlers let yardmaster Connie Hooper (Rosario Dawson) know that that they have a runaway train headed into opposing traffic on the main line. Assuming the dead man's switch will trigger the brakes and turn the train into a "coaster" that stops a few miles from the yard, she tells them to catch up with a speeder and stop it. She also calls Ned (Lew Temple), a welder for the railroad, and tells him to set a switch. When he arrives at the switch, after waiting some minutes, the hostlers arrive, and it becomes clear that the train has passed already, moving faster than expected due to being under power. The hostlers proceed to catch up with the train, but do not succeed in boarding it.
Connie and the dispatchers work to get every train on the main line onto sidings. Oscar Galvin (Kevin Dunn), Connie's superior, calls her and asks her what's happening and what she's doing about it. She hasn't yet figured out how to stop the train, but works to make sure that each of the grade crossings along the line are secured, since 8 of the tank cars on the runaway train collectively contain 80,000 gallons of molten phenol, a hazardous material.
On their train, Barnes and Colson hear the dispatcher's order to pull into a siding. Barnes says they can't use the siding initially assigned since the train is too long to fit in it. He asks instead if an RIP track further down the line is clear and gets permission to continue along the main line to it.
Galvin overrules Connie's suggestion to derail the train in an area of lightly populated farmland, since it would be too costly and it is still possible to stop the train. An emergency meeting of railroad executives approves another plan, but Galvin refuses to tell Connie what it is. The train's odyssey becomes a media event, followed by helicopters with continuous coverage on television and reporters at crossings in small towns.
The company's plan, to have a lashup of two locomotives enter the main line ahead of the runaway and slow it down while another employee attempts to board the lead locomotive from a helicopter, fails catastrophically, leading to the derailment of the lashup locomotives and the death of the veteran engineer operating them, Judd Stewart . The police abort another plan of triggering the safety switch on the locomotive's side with close-range shotgun blasts at a grade crossing when they realize the switch's proximity to the fuel tank. Barnes and Colson make it into the RIP track in the nick of time, as the runaway smashes through the rearmost car of their consist.
As the train passes, Barnes sees that the coupling on the last car of the runaway is open. He decides to put his locomotive in reverse and catch the runaway by coupling onto the back of it. Colson, at first reluctant, joins him. Galvin insists that Barnes, Colson, and Connie abandon the plan, but they refuse even after Galvin threatens to fire them. Barnes then reveals that he has already been fired by Galvin, forced into early retirement.
Another attempt to stop the train with derailers in a small town fails because the train is too heavy and going too fast. Evacuations begin as the train approaches Stanton, where the line crosses the town on a sharp elevated curve. Taking the curve at the runaway's current speed would result in it derailing and falling into a fuel oil tank farm, causing a major disaster.
Barnes and Colson catch up with the runaway. After Colson manually couples their locomotive to the train, they begin slowing it down with their own brakes, but are unable to slow the runaway down enough to safely navigate the curve. Barnes goes out onto the train and begins setting each car's brakes manually, but is stopped at a gap between two cars that is too wide to bridge. Colson then applies an independent brake from the chase locomotive. These two factors slow the train down just enough to get it through the curve with precarious tilting, rather than a derailment. After coming out of the curve, however, the chase locomotive's brakes blow out and the train begins to pick up speed again.
Ned the welder catches up to the train, and Colson jumps into the back of his truck. Driving at high speed they make it to the front of the runaway, where Colson jumps to the lead locomotive and finally stops the train. Barnes and Colson are declared heroes and reunite with their worried families.
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