In a rail yard within the northern Pennsylvania town of Fuller, a pair of workers for the Allegheny and West Virginia Railroad (AWVR), Dewey (Ethan Suplee) and Gilleece (T.J.Miller), are ordered to move a freight train off its current track to make way for an excursion train carrying schoolchildren. Dewey tells Gilleece not to connect the locomotive's air hose to save time; he does this knowing that the train's air brakes will be disabled on everything behind the gap in this configuration, but resolves to connect the hoses after parking the train on another track. Dewey begins moving the train through the yard, but sees that an approaching switch is not set to the right track. Against Gilleece's advice, Dewey jumps down to line the switch properly, while the independent brake and throttle/dynamic brake levers in the cab, unattended, fall of their own accord to 0% braking and full throttle, respectively. 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 in the southern Pennsylvania city of Brewster, 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. They take their locomotive to a zinc plant outside the city of Stanton to attach their train for the day, where, after Colson makes the mistake of picking up too many cars, they head north on the main line towards Fuller.
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 high-rail-truck and stop it. She also calls Ned (Lew Temple), a lead welder for the railroad, and tells him to set a switch to direct the train into a siding. When he arrives at the switch, after waiting some minutes, Dewey & Gilleece 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. From the AWVR headquarters in Pittsburgh, Oscar Galvin (Kevin Dunn), vice-president of train operations, calls her and asks her what's happening and what she is doing about it. She has not 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 30,000 gallons of molten phenol, a hazardous material.
Barnes and Colson hear the dispatcher's order to pull into a siding. Barnes says they cannot use the siding initially assigned since their train is too long to fit in it. He asks instead if a Repair-In-Place-track further down the line is clear and gets permission to continue along the main line to it.
Galvin rejects 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 let Connie listen in on the meeting. 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 an employee (Ryan Ahern) 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 (David Warshofsky) operating them. Barnes and Colson make it into the Repair-In-Place 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.
The police abort a plan of tripping a fuel cutoff switch on the locomotive's side with close-range gun blasts at a grade crossing when they realize the switch's proximity to the fuel tank. 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 dynamic 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 individually, but the chase locomotive's dynamic brakes blow out and the runaway begins to pick up speed again. Colson then applies an independent air brake from the chase locomotive. These 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, Barnes attempts to run to the lead locomotive, but is stopped at a gap between two cars that is too wide to bridge.
Ned drives up alongside the train in his pickup truck, and Colson jumps into the back. 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, Colson and Ned are declared heroes and the former two reunite with their worried families.
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