August 1943- Nazi-occupied Italy. An American P-38 Lightning fighter plane with smoke trailing from one of its engines sputters and loses altitude above an Italian coastal town. A pair of German officers abruptly interrupt their lunch to catch up with the rapidly descending plane. When the Germans arrive at the crash site, they encounter a burning fuselage surrounded by Italian soldiers. The soldiers explain that the pilot was killed in the crash. Satisfied, the Germans leave. As soon as they are gone, the Italians mock their imperious occupiers and part ranks to reveal a hidden and slightly injured American flyer, Colonel Joseph Ryan (Frank Sinatra).
Ryan is taken to an Italian POW camp filled with British and American prisoners. Italian discipline over the camp is lax and the prisoners are filthy and ragged. Constant escape attempts have enraged the Italian commandant and resulted in the withholding of clean clothes, hot water, razors, and food parcels. The ranking British officer has just died while imprisoned in the camp sweat box. Command has fallen to the irascible British Major Fincham (Trevor Howard) of the Ninth Fusiliers. The pragmatic Ryan and the inflexible Major Fincham immediately clash, with Ryan outranking Fincham and able to coutermand his orders.
With the Americans only weeks from liberating the camp, Ryan wants all futile escape attempts stopped. He betrays the active escape tunnels to the Italian commandant, Major Battaglia (Adolfo Celi), earning both the enmity of the British prisoners and the scornful nickname "Von Ryan." As a reward for Ryan's cooperation, Battaglia turns the showers back on and issues razors and Red Cross parcels. But he balks at issuing clean clothing, since he is selling the donated clothes on the black market. Ryan orders the men to strip and burn their filthy clothes. As punishment, Ryan is placed in the sweat box while the men receive their clean clothing.
Some time later, Ryan's fellow inmates release him from the box with the welcome news that the Allies have landed at Salerno and Italy has surrendered. The Italian guards have fled, but Major Battaglia has been captured. Major Fincham intends to convene a court martial before summarily executing him. Ryan intervenes, countermanding Fincham's orders and directing instead that Battaglia be confined in the sweat box. Fincham is furious and again accuses Ryan of treachery. Battaglia's second-in-command, Captain Oriani (Sergio Fantoni), tells the group that the Germans will soon be coming to recapture them, and he offers to lead the men to safety.
The camp's 400 former inmates pour out of the stockade behind Oriani. German troops occupy the main roads, so the men are forced to travel through the woods, stopping for the night in some abandoned ruins. Captain Oriani goes ahead to scout out an escape route. Meanwhile, the Germans reach the empty prison camp and hear furious knocking from inside the sweat box. Battaglia is quickly released, and he informs the Germans of the recent prisoner exodus.
The next morning, the escaped fugitives are quietly surrounded by German troops. Those prisoners who try to flee are gunned down, and the rest are marched to a nearby rail siding. The ambulatory prisoners are loaded onto boxcars while the sick and wounded are shot. Aboard the train, the men discover a severely beaten Captain Oriani. The train is apparently headed for a prison camp in Germany. More bitter recriminations are directed toward "Von Ryan" for his decision to spare Major Battaglia's life.
The train stops in Rome, where the prisoners are offloaded and fed. Back on board the train, Major Fincham continues his steady stream of invective against Ryan. He sarcastically comments that they won't be able to "tunnel" their way out this time. The intended insult gives Ryan the idea for a desperate escape plan. Each boxcar is guarded by a German soldier riding on top, armed with a machine pistol. A couple of the floorboards in Ryan's boxcar are prised up so that there is a way to drop to the tracks below. After another brief stop and under the cover of darkness, the prisoners lower themselves one at a time from the slowly rolling train until their heels are dragging over the rail bed below the car. Then they allow themselves to fall flat on their backs as the cars pass over them. At the right moment, each prisoner rolls quickly between the wheels and over the rails, then springs upright to catch up with the nearest car. Once mounted on the ladders between cars, the prisoners are positioned to climb to the roof and crawl up behind each guard, strangling him with a rope. Ryan kills the first guard in this manner, appropriating his helmet and machine pistol. When the train stops again, Ryan orders Fincham to free other prisoners from the locked boxcars and attack the remaining guards. The prisoners are soon in command of the train, but just as they get underway they hear another train approaching from behind. The captured Wehrmacht officer aboard the prisoner train informs Ryan that it is a German troop train on the same schedule as their own and heading for the same destination- Innsbruck, Austria.
Now the fleeing men must find a way to redirect their train toward neutral Switzerland, not an easy task when the rail lines and rolling stock are controlled by the Nazis. Many tense situations will have to be overcome as the action moves toward a violent climax high in the Italian Alps.