Mike's 20th Anniversary is interrupted when he and Jerry are summoned by their company to haul a top-secret government load to Buffalo. The job proves to be extremely dangerous when enemy agents overcome their police escort.
While hauling a dangerous cargo of nitroglycerin on winding mountain roads, Mike swerves to avoid striking an animal, sending his truck into a ditch and blowing out a tire in the process. While Mike trudges off to find help, Jerry tries to replace the flat, but gets pinned under the truck in the process.
An escaped convict kidnaps his niece and nephew from an orphanage where they have been since their father's recent death. the kids try to elude their unhinged uncle by stowing away on Mike and Jerry's truck. Discovering them, Mike takes the kids home for the night, but the Uncle is stalking them.
Mike's love of truck-stop food has often resulted in his getting mild cases of indigestion, so when he complains to Jerry about stomach pain, Jerry just figures it's Mike's stomach acting up again. It turns out to be more serious than both of them think, however, and Mike winds up being rushed to the hospital by ambulance.
After a C&A truck driver's son dies, his wife deserts him and he loses his job with the shipping company, the man blames all his problems on Mike Malone. The fired trucker determines to get revenge by blowing up Malone's rig with a homemade bomb and killing Mike in the process, but Mike's son intervenes.
Ben Handley, a man Jerry Austin detests, is selected to be the trucking company's new parts manager. While giving him a lift to Buffalo, Jerry and Mike discover that Ben knows absolutely nothing about truck engines. Furthermore, he has a serious drinking problem. When the truckers encounter an accident where the driver has been seriously injured, Ben suddenly displays hidden medical skills and takes charge of saving the dying man.
A female reporter asks the C&A Trucking Company to allow her to go on a long-distance trip with one of their crews. Believing it would be good publicity, the dispatcher assigns Mike and Jerry to escort her, but everything on the trip goes wrong.
A female reporter asks the C&A Trucking Company to allow her to go on a long-distance trip with one of their crews. Believing it would be good publicity, the dispatcher assigns Mike and Jerry to escort her, but everything on the trip goes wrong.
Truckers often use caffeine pills to stay awake during long hauls. However, some truck stops are selling "stay-awake" pills that can not only keep a driver awake but can kill him. Mike and Jerry decide to help the Highway Patrol break up this pill racket.
A hitchhiker overhears Mike and Jerry discussing their tiny but valuable cargo - a small piece of iridium worth $100,000 and decides to break into their truck and steal the rock. The thief doesn't realize that the iridium is radioactive and will kill anyone who carries it outside its lead box for more than three hours.
When Jerry is accused of stealing and fired from his job at C&A Transport, he is actually working undercover with the police to recover stolen goods from the company's warehouse. Mike decides to do some investigating of his own and nearly jeopardizes the investigation and Jerry's life.
During World War 2, Mike had to shoot one of his own men to stop him from slaughtering prisoners-of-war. When he learns that a wounded veteran is searching for a trucker nicknamed "Cannonball", he fears that the man he shot has returned and is seeking revenge
Mike and Jerry pick up a burly man and his crippled son who are walking along the side of the road. Stopping at a diner for lunch, the father is challenged to a fight, but refuse, causing his son to lose all respect for him. The truckers try to restore the youngster's faith in his father.
Defending champion Mike Malone, decides not to defend his title at the annual "Roadeo", a competition where truck drivers pit their driving skills and knowledge of safety regulations, believing that Jerry should be given a chance to win. Unknown to both men, another trucker plans to sabotage the other contenders chances so he can take home the top prize
Mike witnesses a murder and identifies to killers to the police. When reporters leak the story to their newspapers, Mike becomes the target for another gangland killing.
Mike and Jerry come across a trucker they know badly beaten. He reluctantly tells them of a nefarious protection racket that's been shaking down independent operators, all of whom are too intimidated to talk to the police or Mike. Though little does he realise, that his erstwhile friend and victim is the brains of the gang.
When Mike learns that Jerry has turned down a full four-year scholarship to a prestigious engineering school because the younger man doesn't want to break up their partnership, Mike fakes eye trouble and flunks the vision exam so that he will be forced to take a desk job.
