While searching for the man who framed him for a crime he didn't commit, Destry stumbles into a town where an old cell mate of his is being tried for robbery and murder. The outlaw has hidden the loot and offers to reveal the location to Destry who doesn't wish to be trailed by detectives trying to recover the mine's stolen gold for the rest of his days. Instead the outlaw provides the location to a gold digging saloon singer.

After mild-mannered Clarence Jones rescues him from renegade Indians, Destry agrees to accompany the man to a wide-open boomtown run by criminals to claim the ranch he inherited from his deceased brother. Clarence learns that his brother's valuable spread was lost in a poker game to one of the town's shady characters under suspicious circumstances.

While searching a small Colorado town for the man who framed him for robbery, Destry runs afoul of the local sheriff who runs him out of town for vagrancy. At the train station, Destry meets an elderly bank teller who has used the town's Law and Order Day celebration as a cover to steal all of the bank's cash from it's vault and make her getaway.

Destry stops into a ghost town to visit his old friend, saloonkeeper Bessie Hawkins and the young girl she raised as her own daughter after her mother died in childbirth. Destry tries to help the pretty woman deal with a the child's wealthy real-life grandfather who has journeyed from Boston to take her back and a spurned suitor who plots with two drifters to kidnap the youngster.

Destry blunders into a saloon shout-out which leaves the participants dead or mortally wounded. The dying miner creates a last will and testament bequeathing his jar of gold dust to the most worthy person in the boomtown and, before expiring, names Destry to be his estate's executor. Destry soon discovers he has a lot of new friends and a couple of new, deadly, enemies.

Destry agrees to help a pretty teacher raise funds to build a school for need Cherokee Indian children. The schoolmarm's plan is to utilize her foolproof mathematical formula to win at various forms of gambling, but Destry soon learns that the shady casino owners don't like losing, even if they have to resort to crooked means to derail the pretty blonde's string of luck.

When her father and his men break up Sheba Hannibal's plans to elope, the young woman claims that Destry is really her fiancé, Curly Beamer and while the elder Hannibal and Destry argue Sheba escapes to meet the real Curly. Destry is hired to pursue the pretty blonde and discovers that Sheba's "boyfriend" is really the leader of an outlaw gang who plan to hold her for ransom.

Destry rides into a small town to visit its sheriff, an old friend of his father's, not knowing that the Flanzig brothers have escaped from prison and threatened to burn it to the ground for breaking up their bank robbing gang and sending them to prison 18 years earlier. Needing a deputy, the sheriff tries to trick the young man into helping him fight off the outlaws.

Destry career as a photographer's assistant is cut short when his friend and employer, Jim Logan, is murdered during a bank robbery. When a U.S. marshal asks for Destry's assistance is solving the crime, the cowpoke decides to use his reputation as an ex-convict to track down the outlaws and give the reward money to Logan's widow and children.

Destry is mistaken for a member of the Jellico family and is shot and severely wounded by the Motleys by accident. Doc Finley manages to save Destry's life with a transfusion of blood contributed by Jethro Jellico. When the Motleys find out is carrying some of Jethro's blood in his veins, they threaten to kill him on sight.

When Destry drops by a cellmate's Wyoming ranch for a visit, he is almost caught in a crossfire between his friend's would-be criminal son and the local sheriff who's convinced that the ex-con has resumed his life of crime. Destry tries to use the teenager's criminal ambition as a lever to convince his old friend to leave the outlaw trail while simultaneously leading the sheriff's posse to the gang's hideout.

While visiting a Colorado cowtown, Destry bumps into an old friend, Pete Daley, who offers the ex-convict a thousand dollars if he can protect him from a pretty girl who's determined to marry him while the businessman is in town trying to close a big deal. Destry's mission is complicated by the two things - Pete loves the young woman and can't remember anything he says or does when he's under the influence of champaign.

After losing all his money in a poker game, Destry is conned into driving a wagon full of bibles to a mission three days south of town for which is he offered the princely sum of fifty dollars to take the job. The man who hired him, however, neglected to tell him that he had to drive his freight through Comanche territory - and the Indians were on the warpath.