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.

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.

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.

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.

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.