Fred has promised Frank some hard-earned time off, yet always finds some way to lure him into another stage run instead. This time he pays an actor to impersonate the husband of a girl Frank was anxious to meet. Souring on her, he agrees to the next job. That job turns out to be a special mission to transport captured outlaw Cole Younger to trial, all incognito. Adding to their worries, Johnny coaxes Frank into hiding a fortune in gold in the coach without Fred's knowledge. At a way station, a supposedly dying woman is allowed to board, to rush her to a doctor, but ...
Fred Kelly agrees to deliver The O'Mara, his four beautiful card dealers and their gambling equipment to Carson City where the Irishman plans to open a casino. Fred thinks his biggest headache will be keeping Flip Flippen's mind on his job driving the stagecoach, but his biggest problems turn out to be an outlaw gang after the $20,000 in gold that The O'Mara has stashed in his luggage and the denizens of the Nevada mining camps who want to force to dealers to become their wives.
Fred Kelly agrees to get Flip's pretty fiancée a job as a schoolteacher if the young man will forge a new stagecoach route to called Mesa Flats. The arduous journey to the boomtown, during in which Flip and his men have to battle Indians and outlaws causes the transplanted Easterner to reconsider matrimony and her choice of vocation.
The Overland Stage is hired to transport Cattle Kate Maxwell to a federal prison and her date with a hangman. Flip Flippen is unhappy with the mission and comes to believe that his pretty prisoner could possibly be guilty of the crimes she was supposed to have committed. He decides to pretend to let her escape in hopes she will either prove her innocence or lead him to the rest of her outlaw gang.
Kelly and Flip must chance making a stagecoach trip to Sacramento even though Sioux renegades have made the road west extremely hazardous. Although the passengers of the trip's danger, a number of them are determined to make the journey, including a doctor pursued by a murderous bounty hunter and a rival for the Overland Stage's mail contract who is determined to sabotage the run.
Kelly's efforts to open a stagecoach line from Carson City to Payload hit a snag when he learns that his old rival The O'Mara has established himself as the mayor, sheriff and town boss of the boomtown. The Irishman has established a rival company and, with his municipal powers, has impounded all of the horses in the vicinity unknowingly hiring an outlaw gang as his deputies to enforce his edicts.
Before Kelly travels to St. Louis for some business meetings, he appoints Flip acting superintendent with instructions to open a new branch line into the Black Hills. Flip quickly runs into trouble with the Sioux Indians when he agrees to take the pretty half-Sioux daughter of a white trapper to a girls' finishing school against the young woman's wishes - and those of the Sioux brave who is determined to marry her.
Flip is lured away from Overland Stage company by a beautiful but unscrupulous female attorney to help her press her claim for part of a valuable gold mine willed to her by her father. The miner's will be be contested in a town that has no use for the Flip or the lawyer, but Flip is determined to win a judgment without resorting to crooked tactics proposed by his associate.
Kelly and Flip go undercover as notorious bandits to penetrate Montana outlaw gang who had been robbing Overland Stage conveyances and stealing gold shipments. The Virginia City vigilante committee suspects that the brains behind the robberies is a well-respected businessman and the evidence seems to indicate that one of the town's lawmen might be involved.
In competition with another stagecoach line that continually cuts their prices, Kelly determines to make his cuts in another way by boring a tunnel through a mountain to shorten the route between stops by three days. His task is complicated by sabotage and his crew being distracted by a pretty blonde who owns a tent saloon.
The ambassador to Mexico requests that the Overland Stage company provide transportation to a Mexican diplomat on a mission of vital importance to both the United States and Mexico. The diplomat, the beautiful niece of Emperor Maxmillian, seeks American assistance combating revolutionaries seeking to overthrow the French-supported regime. The revolutionaries plan to kidnap the princess before she can enter United States territory and appeal to Flip for help.
Kelly is determined to win the lucrative contract for the Overland Stage to deliver the U.S. Mail to Denver, Colorado, but his competition for the run is pretty stiff. The contract will be awarded to whoever makes the quickest trip and the Overland Stage's rival has imported a light Austrian stagecoach used in the Alps and hired famed driver Calamity Jane to handle the horses for the big race.
Sour Annie Tatum, an experienced female prospector, agrees to help Kelly, Flip and their men capture wild horses in exchange for a free ride into town. Annie is thrown from her horse during the roundup and badly, if not mortally injured. Flip and Harlan, one of the wranglers, agree to stay with the old sourdough until she dies, but the wrangler, knocks Flip unconscious, steals Annie's gold, guns, and horses, leaving the young stagecoach driver and old prospector alone and defenseless in the desert.
A timely warning from a Jack Morton helps Kelly and Flip fend off the attack of a pair of would-be thieves. In gratitude, Kelly offers the man a free ride on the Overland Stage to whatever destination he chooses. At the next way station, Morton meets a farmer and his pretty daughter and sells them a tract of worthless desert. When the swindler has a change of heart, Kelly agrees to help him make restitution.
The Overland Stage is hired to transport Aloka, the wife of Crazy Horse, and a proposed peace treaty to the Sioux Indians for ratification. Renegade warriors attack the stagecoach to prevent the treaty from being consummated, but are driven off. Flip agrees to guide Aloka's cavalry escort to Crazy Horse's village, not realizing that the commanding officer wants to kill the Sioux war chief to avenge his brother's death at the Battle of the Little Big Horn.
Acting on information provided by a sleazy newspaper reporter, blind Anne Michaels travels on the Overland Stage to find her son whom she had lost track of years before. Along the way, an outlaw gang tries unsuccessfully to rob the stage and Flip is forced to gun down one of the attackers. Flip learns that the man he shot was the blind woman's son and tries to make amends.
When Palmer, Kelly's commanding officer during the Civil War, asks for help, the old Irishman is happy to oblige - especially since one of his employees is killed by a shotgun blast meant for the former general. Palmer explains that a rival railroad is trying to prevent his company, the Denver and Rio Grande, from making a successful trip to Leadville and will stop at nothing - even killing their passenger, President Ulysses S. Grant, to put him out of business.