Story concerns the efforts of Buffalo Bill to protect the Indian's land from a gang who want to get the gold buried there. The outlaws disguise themselves as Indians and raid and plunder the settlers in order to blame the tribe.

A major Indian uprising is expected and Wyoming military posts are alerted. Colonel Dennison is meeting with Chief Eagle and his son Running Wolf when Chief Eagle is mysteriously shot. Steve Holden, an agent for the government peace commission, with the aid of a wandering shoemaker, Smiley, discover the troubles and the Chief's murder have been instigated by Cronin, the regimental scout, for personal gain for he and his gang of outlaws.

Produced by Jack Schwartz for low-budget company Screen Guild, this mild Western starring the veteran Richard Arlen was apparently the first entry in a proposed series. Arlen played the title role, here assigned by the army to quell an Indian attack on the powerless settlers. The Indians are accusing Tom Russell (John Dexter) of murdering a member of the tribe, an act, as Buffalo Bill discovers, actually committed by a gang of outlaws hired by investment company owner J.B. Jordon (Frank O'Connor). Buffalo Bill Rides Again was soundly defeated by a low budget and slipshod direction by the veteran Bernard B. Ray. Popular B-Western villain Ted Adams disappeared mysteriously halfway through the film, only to be replaced by Edmund Cobb. Jennifer Holt, the daughter of Arlen contemporary Jack Holt and by far the busiest B-Western heroine of the 1940s, had little to do other than letting herself be kidnapped by evil Gil Patric.