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While moving a train pulled by engines #777 and #767 at the Veteran Allegheny and West Virginia Railroad (AWVR) trainyard in the fictional city of Fuller, Pennsylvania, the two hostlers, Dewey and Gilleece, take ill-advised shortcuts and accidentally allow the engine to leave the trainyard on its own power without the air brakes engaged. Initially believing the train to be a "coaster", yardmaster Connie Hooper orders Dewey, Gilleece, and chief welder Ned Oldham to drive and catch up the train to stop it. When Oldham finds that the train has already passed where it was supposed to be, they realize that the train is running on full power and now poses a dangerous threat. Dewey and Gilleece manage to catch up to 777 using a high-railing truck, but fail to board the train in time. Hooper alerts Oscar Galvin, director of operations for AWVR, as well instructs the local and state police and sheriffs to secure all the grade crossings to prevent injury. Visiting Federal Railroad Administration safety inspector Scott Werner finds that 8 cars being pulled by 777 contain molten phenol which would be a major disaster if the train should crash or derail in a populated area. News of the runaway train soon becomes a media event.
Hooper suggests they purposely derail the train, but Galvin disagrees and believes they can safely stop the train by lashing it behind two slower-moving diesel engines helmed by veteran engineer Judd Stewart, slowing it down long enough for AWVR employee and former U.S. Marine Ryan Scott to descent from helicopter to 777's cab and stop the train manually. Though the lashing initially works, 777 jumps ahead, knocking Scott out and derailing the two diesel engines, causing them to explode, which ultimately kills Stewart in the process. They realize that 777, traveling at its current speed, will certainly derail on "Devil's Curve", a tight, elevated portion of track in the middle of the city of Stanton on the eastern side of the state. Plans are made to purposely derail the train outside the town of Arklow using derailers.
Meanwhile, retiring AWVR engineer Frank Barnes and conductor Will Colson, a new hire, are pulling several cars with engine #1206 from Stanton. Though originally aware of 777 coasting away from the Fuller train yard, they are ordered at the last minute to pull into a Repair-In-Place track, making it just in time as 777 races by and clipping the last few cars they are pulling. Barnes observes that 777 has an open knuckle, which if they could catch up to the engine, they could use to couple to 777 and use their own brakes to slow the train before it reaches Stanton. As Colson unhitches their cars to give them the best chance of catching up, Barnes reports his plan to Hooper and Galvin and warns them that the derailing idea will not work given 777's momentum, but Galvin threatens to fire Barnes if he continues. Barnes ignores Galvin and sets 1206 on course to catch up with 777. As 777 passes Arklow, police attempt to shoot the fuel shutoff switch on the engine, but fail to hit it. As Barnes predicted, the train barrels through the derailers without slowing down. Hooper and Werner fully support Barnes' plan and take over control of the situation from Galvin.
Barnes and Colson catch up to 777 and manage to engage the coupling. Barnes attempts works his way across 777 to its cab while Colson engages 1206's dynamic brakes, which initially slow down 777, but would prove to be no match for 777's speed. They are able to reduce the speed slow enough to clear the Stanton Curve without derailing by using the independent brake, but 777 remains out of control and threatens to crash into the Stanton train yard. Barnes finds his path blocked to 777's cab, but Oldham arrives in his truck with a police convoy and drives on a parallel road to the tracks. Colson jumps to Oldham' truck, and Oldham drives him up to the front of 777 allowing Colson to get into the cab and engage the brakes. 777 is safely stopped before it reaches the end of the line.
Barnes, Colson, and Oldham are heralded as heroes, Hooper is promoted to Galvin's former position for her leadership, and Dewey goes into work into the fast food industry, indicating he was fired.