A passenger becomes ill and it is realized he has smallpox meaning all the passengers on the train are in danger. Casey needs to get life saving drugs but no town will let them stop.

Casey is accused of destroying a farmer's crop as a result of sparks from the speeding Cannonball Express. Although he is suspended during the investigation, Casey decides to take the Cannonball on a test run to find out about the truth of the claim.

The president of the railroad wants to see Casey urgently after a train wreck occurred during a railway strike. He is instructed to take a United States Marshall and a star witness non stop to Denver. During a run through a tunnel, the Marshall is shot. The witness explains she is aware of a gang, the Worker's 7 who caused the wreck, and they may be after her. A desperate race against time develops as Casey tries to find a bomb hidden somewhere on the train while keeping to his tight schedule

Casey is commissioned by the Mexican government to carry a special shipment of Emperor Maximilian's crown jewels to St. Louis but the Secret Service agent guarding it on the Cannonball Express is an impostor planning to steal the treasure.

Casey stops at Jamestown to discover the local dispatcher has been arrested for murder. Complications arise when it is discovered the arresting marshal is the brother of the man who the dispatcher killed.

Casey pushes the Cannonball through a night of torrential rain till they are stopped by a washed out line, and Casey is forced to wait for permission to switch to another line. As the rain continues, concern grows over conditions at the local dam. Suddenly a simple passenger run has become a desperate rescue effort. The dam finally fails and Casey has to balance the needs of his passengers with those of the remaining families in the area.

A mysterious girl boards the train and fools Casey into thinking she is a defenseless victim. Casey soon discovers the truth of the situation, and goes in search of woman after she has left the train.

Casey comes to the aide of immigrant railroad workers who are being threatened by the local cattleman fighting against the building of tracks across their land.

Due to bad weather Casey's train is canceled. Returning home he discovers two escaped prisoners have broken in and are holding the family hostage. One of the men is in desperate need of medical attention and Casey has to play a delicate game to keep his family safe while complying with the demands of the criminals

Casey is shocked to see the Cannonball sudden drive off with no engineer or fireman. Despite repeated communication with other stations, the train appears to have vanished off the face of the Earth. While searching for his train Casey becomes embroiled in a scheme to move stolen gold using the hidden Cannonball; a scheme that also requires the death of Jones at the hands of someone very close to him

Johnny Ferguson has served his time. But his dreams of starting over are not going to be easy, especially if Luther Wagner has anything to do with it.

Acting under secret orders, Casey wrecks a train to fake the deaths of a Sheriff and 6 deputies. Unaware of the truth, the town folk of Midvale soon turn against their old friend.

Casey races a top gun coachman into Midvale where they are greeted by a US army officer who takes command of the train and coach. The army is transporting a prisoner (Geronimo) to Deadwood and explains to Casey they expect trouble from Indians on the way. At Willow Springs the train is delayed after Indians have killed all the station staff. Finally arriving at Deadwood, Casey volunteers to ride with the stage coach to Gailleville to complete the prisoner transfer. Apache war-bands have other ideas and press home repeated attacks.

It is Redrock's birthday and he discovers he is to be retired. He is at a complete loss as what to do and starts to make vague plans about starting a ranch to help keep him busy.

Casey and the Cannonball Express become unwilling participants in a plot to rob a Military escort of it's million-dollar payroll when outlaws disguise themselves as bank guards.

Casey's train is robbed by a gang of outlaws. A hostage situation develops as the criminals realize the mail they were after is not aboard. To buy time Casey tells them the next train coming through will have what they want. For the next 6 hours Casey has to play a delicate game of divide and conquer with the gang, while keeping the passengers out of harms way

Casey and the Cannonball pull into Midvale and gets an urgent message from Mr. Carter to see him urgently. He is introduced to Bill Maguire, a secret service agent for the President who will be passing through the town the next day. Casey is then offered the job off hauling the Presidents Special out to the start line for the new territories. A second agent Charles Upton is expected in town, but is bush whacked by men wanting to kill the President. Next day Casey and the fake agent take a run on the Cannonball to go over the route to be used by the President. At ...

Jones arrives at Finney's offices to be briefed by Peter Holmes a US treasury official. Jones is due to run a military prison train to Kansas and is instructed to take a load of gold bullion with him. Part way along the trip the train is stopped by damaged tracks. They decide to back the train up only to discover the line behind them is also damaged. A gun battle erupts when a group of outlaws ride in but a driven off by the guards. Casey devises a plan to rebuild the rails. The plan requires releasing the prisoners, who see their chance and make a break for it till ...

A track-walker saves the Cannonball from certain disaster, so Casey offers him a job, but he has a secret past . Russell Johnson plays the track-walker, 7 years before he and Alan Hale Jnr. would be stranded on Gilligan's Island.

A group of outlaws commandeer The Cannonball and prevent Casey and the crew from leaving town, the Sheriff is shot so Casey puts on the badge, but when he asks the townspeople for help only one steps forward. Lee Van Cleef is the bad guy.

A young girls one chance of surviving an attack of appendicitis while on the Cannonball, hinges on the Doctor aboard. The only problem with that is he is a being escorted by the sheriff as a prisoner on his way to jail.

After an old prospector is shot by an outlaw to steal his treasure map, Casey helps the sheriff catch the murderer, but then later discovers that the villain is the wayward son of carpenter Pete Dunlap, one of Casey's best friends.

At an Army outpost, a tough and by-the-book Colonel Bullock, determined to eliminate all Indians, threatens to have two Indian braves executed. As a result, a Sioux war party launches an all out attack on the outpost.

Casey's employer, the Midwest & Central Railroad faces bankruptcy unless it gets a U.S. mail contract for the St. Louis to Ft. Worth run. The catch is that the company that gets the contract must win a train race. The MCRR's track runs through the Ozarks, but Casey still thinks his engine, the Cannonball, is faster than his competitor's, but the Southern & Panhandle Railroad, the rival company, sends saboteurs and gunmen to slow his progress.