George Caldwell (Gene Wilder) is a divorced and mild-mannered book editor that wants to relax and take a train to Chicago for the next 2 days so he can "be bored for a while". Shortly after getting on the train, he meets a friendly vitamin salesman named Bob Sweet (Ned Beatty). Not long afterward, a woman named Hilly Burns (Jill Clayburgh) wants to have dinner with him. He accidentally barged into her compartment next door to his while she was disrobing. The two of them share over 2 bottles of champagne together and stay in the diner until closing. Hilly is working as a secretary for a Professor Schreiner, a semi-reclusive history professor that is about to give a speech at a university. Briefly we see a small group of thugs beating up a bearded man. George and Hilly retire for the night and make love.
Just as she is caressing him, he sees a man fall from the roof of his window off the train. George reacts in horror and Hilly believes he drank too much and hallucinating. George wakes up the next day and finds a book and shows Hilly the photo on the back cover of it, who was the bearded man he saw murdered last night. Hilly says that's Professor Schreiner and still refuses to believe George. She tells him where his compartment is so George can see himself that he's okay.
George passes by Bob Sweet in the dining area, who wants to have breakfast with him, but George says he'll be right back to join him. He knocks on the door of Professor Schreiner's compartment and a sinister looking 60-ish man with a cigarette in his mouth (Ray Walston) answers the door. George says he wants to see the professor and the man tells him he's sticking his nose where it doesn't belong and that he and Hilly are in trouble. George refuses to comply and tries to let himself in. The man tells Reace (Richard Kiel, Jaws in the James Bond movies), a thuggish seven foot tall man that doesn't speak, to get rid of George and without hesitation, Reace opens a door and throws George off the train. George is somewhere in Arizona or New Mexico and frustrated at having been thrown off the train being stuck in the middle of a desert. He finds a farm in the middle of the desert and meets an eccentric, but very warm and friendly old woman named Rita Babtree (Lucille Benson).
She takes George to her single engine crop duster airplane and gives him the thrill of his life a ride in the plane to the next town. He was going to give the local sheriff information about the incident he's witnessed, but by the time they arrive at the train depot, the train is already taking off. George runs to the train and the convention crowd in the back catch him and get him on. They are now approaching the Rocky Mountains on their journey. George is back on the train.
It is now lunchtime and he sees Hilly in the dining compartment with an elegant looking man having lunch with her. Bob Sweet encounters George telling him he wanted to have George join him for breakfast, but now it's lunch. George confesses he was "squeezing tits", which he did when he was at Rita's farm milking a cow and Bob jokes with him about being a horny devil. He tells George that man Hilly is having lunch with is Roger Devereau (Patrick McGoohan), a millionaire art dealer in Chicago. George is now back in his compartment, then opens the door to Hilly's and she tells him she was worried about him, embraces him, and that what he witnessed was a hallucination.
Devereau comes into Hilly's compartment and introduces himself to George apologizing about the incident with him being thrown off the train. Edgar Whiney, the sinister looking man George encountered at Professor Schreiner's compartment is surprised to see George and blames Reace for throwing George off. Then a bearded man (Stefan Gierasch) comes into the compartment telling Deverau the papers have been found. He introduces himself as Professor Schreiner. He tells them he is tired from the stress of the searching for the missing papers and will rest and have a scotch. George apologizes for intruding into their business affairs and goes back into his compartment.
Whiney snickers and Devereau slaps Hilly across the face afterwards. George is in the bar and getting drunk. Bob Sweet comes back in acting like he assumes George is having woman problems. George tells him about what has happened since last night, Bob keeps asking him questions about the people he's dealt with, George is perplexed as to why Bob is asking him all these questions and tells him Schreiner was met just a little while ago and wanted to have a scotch and lie down. It turns out Bob Sweet is actually Stevens, a federal agent. Stevens tells George he's been working on a case for the past 2 years tailing Roger Devereau to get him arrested. In actuality, Schreiner despises Devereau and wants nothing to do with him and a health food nut that doesn't touch alcohol and that the man claiming to be Schreiner is an imposter. He assures George that Schreiner has been murdered and he didn't hallucinate.
Stevens takes George to a storage compartment that Schreiner was probably confronted at, then the top of the train. Stevens walks over to an area that's above George's compartment and finds a piece of torn clothing. George realizes he was right. Stevens knows Devereau murdered Schreiner over something, because Schreiner was going to give a speech about some letters that were going to prove Devereau's art in his gallery were forgeries. George realizes that "Rembrandt letters" were mentioned by the imposter earlier.
George and Stevens go back into his compartment and gets a book he saw earlier with actual manuscripts Rembrant himself wrote over 300 years ago. Stevens is amazed at what he found and that the letters will bring down Deverau's art gallery business declaring him a fraud. He also mentions Devereau had a plane crash in Cologne, Germany two years before killing over 100 people to cover up an art scandal. He tells George to push a button for the porter and to have the train stop in Dodge City to have Devereau arrested. A knock is on the door, Stevens answers, then everything goes dark and shots fired. Stevens has been shot and knows George was the intended target because of his knowledge and to take his gun.
He dies from the wounds. The porter (Scatman Crothers) comes to George's compartment and outraged George shot Stevens. George storms out and tells him he didn't do it. Whiney sees George and surprised he's not dead. Reace sees George, shoots at him, then tries to tail him. Reace looks for him in the storage compartment, then at the top of the train. George confronts him and shoots him off. Shortly afterwards, George encounters a railway signal, bumping into it, holding on, then falling off once again.
George is now off the train once again in Colorado and gets a ride to the sheriff's office in a small town. He meets a fat hayseed Sheriff named Chaunsey (Clifton James). George is rattled and tries to tell Chauncey his story, because the sheriff has never dealt with a murder before. Chanuncey is befuddled by the story, but then gets a phone call. It turns out a federal agent is on the phone wanting George for murder and Chaunsey is surprised and finds George a bit nutty. Chauncey confronts George and pulls a gun on him.
George pulls the gun from the sheriff declaring him for being incompetent and that he's trying to save a life. His deputy pulls up in a police vehicle and George hijacks it pointing a gun at Chauncey and the deputy. George is in the police vehicle driving and a handcuffed man in the backseat gets up and startles him. The man is Grover Muldoon (Richard Pryor), a slick and charming car thief impressed at the way George handled the situation. George tells Grover what he's accused of, but Grover wants to be dropped off and doesn't "deal with the big M". But they stay together.
Grover takes the wheel knowing they will be setting up roadblocks on the Kansas state line and crashes into the cars escaping the police. Hilly is on the train in her compartment and Devereau is questioning her about her involvement with George and she swears they just met, but Devereau assures her, they will take care of her in the meantime until they see George again. George and Grover are at a used car lot attempting to steal a Jaguar. A night watchman pulls a gun on Grover for attempting to steal it, then George tackles the man to the ground knocking him out.
Grover assures him they'll make it in time to Kansas City in the early morning to get George back on the Silver Streak. The entire time driving George is worried if Hilly is still alive. George and Grover arrive at the train terminal in Kansas City. They discover federal agents are at the ticket counter and George is on the front cover of a newspaper wanted for murder. In the movie's most famous and hilarious scene ever, Grover takes George under his wing and purchases a hat, radio, and brown shoe polish from a shoe shiner. Grover's intention is to make George pass as a black man. He's having trouble as George is having difficulty with the rhythm of the blues music and dancing very much like a white man.
George is now wearing Grover's purple sport jacket, the shoeshiner's hat, brown shoe polish on his face, and sunglasses. He comes out of the men's room looking and acting downright ridiculous and Grover hopes no Muslims are there to see them. Grover is asked by one of the agents if he's seen the white man wanted and Grover replies, "No, but if I see any, I'll let you know". George makes it past them and on the train. George goes into his compartment to discover all his personal effects are gone. Grover tells George to give him some cash for him to wear a porter's uniform. George is getting fed up with giving up his money for disguises, but does it anyway. He rinses his face off, then finds Hilly in his compartment.
George is knocked out cold, then wakes up a little while later. Hilly comforts him and tells him that she had no choice but to accept Devereau's plan that Schreiner was killed or else she was going to be killed, too. George had the Rembrandt letters in his jacket pocket and they were taken. The two embrace and are just glad to be back together. Edgar Whiney comes into his compartment pulls out a gun and tells George and Hilly Devereau wants to see them. George and Hilly meet with Devereau in his compartment to join him for breakfast.
Devereau is reviewing the letters and loves their historical authenticity, then gives them to Whiney to put in a safe. He tells George that Professor Schreiner actually killed himself and jumped off the train and that they were actually going to kill him later, but because he refused to cooperate and give them the Rembrandt letters, it messed up their plans. Johnson, the man who played the false Professor Schreiner, comes in the compartment now without glasses, a beard, and foreign accent. It turns out he's an employee of Devereau's and another dangerous man. He tells Devereau they will land in Rockdale within 1 1/2 hours, which is where they plan to get off at instead of Chicago, then leaves. Devereau now very calmly tells George and Hilly that there will be a new scenario that they kill each other in 45 minutes. The porter arrives with toast, marmalade, and coffee. It turns out Grover is playing the role of a porter.
Grover jokes around with and annoys Devereau about how "we aims to please" and "ain't bullshittin' about the cuisine", then pretends to accidentally pour coffee in Devereau's lap with Devereau calling Grover "an ignorant nigger". Grover pulls a gun on him threatening him, then George pulls Devereau's gun from his jacket. George now declares to Devereau that man he had shot was a federal agent and they've been tailing him for the past 2 years. He tells Devereau to go back to the safe and get the Rembrandt letters. George points a gun at Whiney to get the letters out, but Johnson shoots at George and Grover. George and Grover leave the train.
This is the third time George has left the train. George and Grover land in a pond right off the train and apprehended by local authorities. Devereau is now burning the Rembrandt letters in his compartment and Johnson gets back on the train after making a phone call. Their plan is to make the remainder of their trip to Rockdale with no further delays and to get off quietly.
George and Grover are brought to the local police station, but not handcuffed. The local chief (Len Birman) tells George that he knows he's innocent of murder, but he was put on the newspaper for his own protection and that they've been trying to pick him up. Grover pretends he's all shaken up from what's happened and wants to go home. George is given a gun to help the authorities out and save Hilly.
They plan to stop the train off at an undisclosed location before Rockdale and get everybody off so they can arrest Devereau. The train stops and all passengers are let off at Harris Mill Junction. Devereau and his men refuse to cooperate and shoot at the chief and his crew. Grover joins George in the gunfight. Whiney gets shot and Devereau refuses to let him get back on the train. Devereau has Hilly and makes the engineer get the train going at full speed. George and Grover get back on.
While Devereau is trying to fight off the police helicopter crew, George kills Johnson and rescues Hilly. Devereau kills the engineer who tries to escape, then puts a heavy toolbox on the pedal. George disconnects a rear car from the train and he, Grover, Hilly, and the porter are now safe. Devereau is shot by the police twice in the helicopter, then decapitated by an oncoming train. The Silver Streak is now a runaway train and all folks at the terminal are ordered to evacuate the area. The train crashes through a cement wall destroying a gift shop, and much of the station.
Grover drives away in a stolen Triumph sports car that was on display in the lobby and George and Hilly walk off and want to find a park to stay in..