Continuity mistake: When John Candy and Steve Martin are travelling from Jefferson City, Missouri to St. Louis they are seen crossing the Mississippi River to enter downtown St. Louis. This would not have been possible unless the bus driver overshot the entire city and ended up across the river in Illinois.
Revealing mistake: Near the end of the film, when Neal is on the final L train home, we see the train pull away from the station. When Neal returns to the station to find Del, the footage of the train leaving is played backwards - you can briefly see a man walking backwards at the top left of the screen.
Revealing mistake: When the couple is yelling to Del "you're going to kill someone" because he's driving on the wrong side of the interstate, you can see that their car's transmission is in PARK. (00:59:35 - 01:01:05)
Continuity mistake: When Steve Martin gets off of the train in Chicago near the very end of the movie to search for John Candy in the depot, the part of his hair is on the opposite side (left) from where it normally is. There is no apparent wind blowing his hair - it looks neatly parted on the "wrong" side. When he enters the depot, the part in his hair is back to the "correct" side. (01:23:30)
Continuity mistake: When the boss puts his hands on the table at the beginning, between shots they go from being spread apart to very close together.
Continuity mistake: In the beginning when Neal's boss is done looking at Neal's work and is about to state his opinion, we see him holding his glasses in his hand while stretching it out. When it cuts from behind him the glasses are no longer in his hand but he has them hanging from his mouth. (00:01:30)
Continuity mistake: When Owen arrives at the hotel to meet Neal and Del to drive them to the train station, Owen is wearing gloves on both hands. As he introduces himself and shakes their hands, Owen's right hand is now bare even though there wasn't enough time to remove the glove. (00:33:55)
Continuity mistake: When Neal and Del are sitting at the counter eating breakfast at the Braidwood Hotel, talking about how they were robbed the night before, watch the plate of food in front of Neal. The food on the plate changes completely.
Continuity mistake: When Dell and Neal get dropped off to catch the train, there is a shot of the town they depart from. Later in the film, when their burned-out car is impounded, they catch a ride on a semi carrying dairy products, departing from the same town.
Factual error: If they are really in the Wichita, Kansas airport, listen carefully to the airport announcements (real faintly in the background). When they say for "Mary Ellen" to meet her party upstairs, there's a slight problem with that. There is no upstairs in the Wichita airport. (00:12:53)
Continuity mistake: The size of the bed in Neal and Del's motel room changes overnight.