Veteran Allegheny and West Virginia Railroad (AWVR) engineer Frank Barnes (Denzel Washington) oversees his co-worker, freshly hired conductor Will Colson (Chris Pine) as they use AWVR locomotive #1206 to run a train outside the fictional city of Stanton, Pennsylvania, but leave with several cars more than they should have because Will added five cars.
Meanwhile, down the line near Fuller, Pennsylvania, AWVR hostlers Dewey (Ethan Suplee) and Gilleece (T. J. Miller) are ordered by dispatcher Bunny (Kevin Chapman) to move a freight train led by locomotives #777 and #767 off its current track. To speed up the short trip, Gilleece leaves the hoses for the air brakes disconnected. Dewey leaves the moving cab to throw a misaligned rail switch, but because of Gilleece's error the train's throttle sticks and the train, now unmanned, begins speeding down the main line toward Stanton. Dewey is forced to report the train as a "coaster" to Fuller yardmaster Connie Hooper (Rosario Dawson), who orders Dewey, Gilleece, and lead welder Ned Oldham (Lew Temple) to intercept the train at a siding. However, the three cannot get to the train before it reaches the siding as it is going too fast.
Ned is ordered to resume pursuit and gets a police escort to help him, while an attempt to regain control of 777 by Dewey and Gilleece from a hi-rail pickup fails.
Connie reports the runaway to Oscar Galvin (Kevin Dunn), vice-president of train operations for AWVR, and coordinates with local police, sheriffs, and Pennsylvania State Police to ensure all grade crossings along the line are secured. Visiting Federal Railroad Administration safety inspector Scott Werner (Kevin Corrigan) alerts them to that molten phenol is being carried by eight tanker cars on the train and poses an immediate danger. Galvin rejects Connie's suggestion to derail the train in an area of unpopulated farmland before it enters the towns ahead, more worried about the damage the derailment would mean to AWVR than innocent lives, believing they can stop the train safely before then. As the train's odyssey becomes a media event, a lashup of two engines, locomotives #7375 and #7346, driven by veteran conductor Judd Stewart (David Warshofsky) goes ahead of the runaway to try to slow the train while AWVR employee and former U.S. Marine Ryan Scott (Ryan Ahern) is lowered to 777's cab from a helicopter. The plan goes awry, injuring Ryan when the train accelerates after he lands on it, and the lashup derails trying to divert 777 to a siding and explodes, killing Judd.
As 1206 heads towards Fuller, Frank radioes in and learns about 777 from Connie. 1206 is on the same track and needs to get off of it, but due to Will's earlier error Frank has to bypass a siding in favor of a longer Repair-In-Place track further along the line. They make it into the RIP siding track as the runaway speeds past them, smashing through one of the rear cars. Frank gets out of the cab of 1206 and realizes that if he unhooks 1206 and goes in long hood forward in the direction that 777 was headed, he and Will might be able to slow the runaway before the train reaches a sharp elevated curve in Stanton, which would derail the train and cause it to crash into several large fuel tanks just below the curve, which would bring massive damage to the town. Will decides to help after some cajoling from Frank, who learns that Galvin is planning to use derailers to stop the train.
Frank tells Galvin directly that the plan will not work and despite the wishes of the railroad, he plans on going ahead with his plan to catch up to 777 on his own. Galvin threatens to fire Frank and Will if they continue, but Frank reveals that AWVR is forcing him to take early retirement and it does not matter. Despite Galvin's demands, Connie and Scott encourage Frank and Will to continue their pursuit.
Outside the smaller town of Arklow, Pennsylvania State Police try to hit the fuel shutoff button with their M16s as 777 passes their grade crossing. They fire several rounds off before ceasing fire at the risk of hitting the diesel fuel tank next to the button.
As Frank foresaw, Galvin's plan to derail the train outside Arklow fails as the train blows right through the derailers. Galvin is left dumbfounded by the failure of the derailers and has no choice but to rely on Frank and Will. Meanwhile, the area around the curve in Stanton is evacuated as 777 approaches as Ned continues his pursuit of the runaway with his police backup.
1206 finally catches up with 777 and Frank and Will are able to hook onto 777's rearmost car despite Will wedging his foot in between the coupling at first. Though 1206's dynamic brakes begin to reduce the speed of 777, the train is still moving too fast for the curve. 1206's dynamic brakes then blow out, and the runaway 777 begins to pick up speed again dragging 1206 with it. Frank goes out and begins to engage each car's manual brakes in a last ditch attempt to slow 777 down as it nears the curve, eventually planning to get into the cab and stop the train there. Meanwhile, Will uses 1206's independent brake to keep the train on the rails as it speeds through the curve. Although the train makes it through the curve without falling from the track, 777 is still out of control and to make matters worse, Frank encounters a gap in between cars that is too wide to cross and thus cannot get to the cab.
Ned arrives in his truck, and pulls onto a parallel road next to the line. Will jumps onto the truck, and is driven to the front of the train, where he jumps into 777 and is finally able to stop the train. Frank, Will and Ned are celebrated as heroes, and the two reunite with their families. A pre-credit montage reveals that Frank was promoted and is now retired with full benefits, Will is expecting a second child with his wife, Connie was promoted to Galvin's job, Ryan Scott recovered fully from his injuries, and Dewey is now working in thefast food industry.
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