The series initially starred veteran movie supporting actor Ward Bond as the wagon master, later replaced upon his death by John McIntire, and Robert Horton as the scout, subsequently replaced by lookalike Robert Fuller a year after Horton had decided to leave the series. The series was inspired by the 1950 film Wagon Master directed by John Ford and starring Ben Johnson, Harry Carey Jr. and Ward Bond, and harkens back to the early widescreen wagon train epic The Big Trail starring John Wayne and featuring Bond in his first major screen appearance playing a supporting role. Horton's buckskin outfit as the scout in the first season of the television series resembles Wayne's, who also played the wagon train's scout in the earlier film.

Frank McGrath
Charlie Wooster

Terry Wilson
Bill Hawks

Robert Horton
Flint McCullough

John McIntire
Christopher Hale

Ward Bond
Major Seth Adams

Denny Miller
Duke Shannon

Robert Fuller
Cooper Smith

Michael Burns
Barnaby West
Chick Hannan
Wagon Train Member (uncredited)
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Have Gun, Will Travel73%
Wanted: Dead or Alive70%
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The Young Riders73%
The Rifleman71%
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Into the West79%
Cheyenne61%
Dr. Quinn, Medicine Woman76%
Vegas70%
Walker, Texas Ranger70%
When Calls the Heart82%
Spirit: Riding Free78%
Centennial76%
The Life and Legend of Wyatt Earp67%