Katharine Hepburn was originally sought for the role of Mrs. Lowe, but turned it down due to Wayne's work as President of the right-wing Motion Picture Alliance for the Preservation of American Ideals. Ironically, more than twenty years later Hepburn did act with Wayne in Rooster Cogburn (1975).
According to TCM, John Wayne won the well-trained dog Sam from his owner/trainer in a poker game after the movie wrapped.
John Wayne was originally to be only the producer of Hondo for his Batjac company, and wanted Glenn Ford for the title role. But Ford had such an unpleasant working experience with director John Farrow on their previous collaboration, Plunder of the Sun (1953), that he turned down the offer. So Wayne then took on the role himself.
In the "Married with Children" (1987) episode "Assault and Batteries," Al Bundy says that Hondo is his favorite movie of all time, and he spends the entire episode trying to watch it in peace.