The song tells a folk tale of a cowboy who has a vision of red-eyed, steel-hooved cattle thundering across the sky, being chased by the spirits of damned cowboys. One warns him that if he does not change his ways, he will be doomed to join them, forever "trying to catch the Devil's herd across these endless skies". Jones said that he had been told the story when he was 12 years old by an old cowboy friend. The story resembles the northern European mythic Wild Hunt.
More than 50 performers have recorded versions of the song. Charting versions were recorded by Vaughn Monroe ("Riders in the Sky" with orchestra and vocal quartet), by Bing Crosby (with the Ken Darby Singers), Frankie Laine, Marty Robbins, and Johnny Cash. Other recordings were made by Peggy Lee (with the Jud Conlon Singers) and Spike Jones and his City Slickers. Gene Autry sang it in the 1949 movie, Riders in the Sky. Children of Bodom, Impaled Nazarene and Die Apokalyptischen Reiter have also made covers.
According to Robby Krieger, it inspired the classic Doors song "Riders on the Storm." The Doors also covered Ghost Riders in the Sky.
The song was also the inspiration for the Marvel Comics character "Ghost Rider."
The chorus lines of this song are and have been since the 1960's a terrace song of the Aston Villa Football Club of England. The words have been modified to include the line "Holte Enders in the Sky" a reference to the occupants of the vast stand behind the goal at the southern end of the Villa Park stadium.