The John Forsythe Show began as a situation comedy in the fall of 1965 on NBC, but at mid-season it switched to a spy show. In the first phase of the series, John Forsythe appeared as United States Air Force veteran John Foster, who inherited the private Foster School for Girls in San Francisco, California, from his late aunt, Victoria. Forsythe's co-stars were Elsa Lanchester as the principal, Miss Culver; Ann B. Davis, as the physical education teacher, Miss Wilson; and Guy Marks as Ed Robbins, Forsythe's aide and a former sergeant. Actors who portrayed students included Pamelyn Ferdin as Pamela, Darlene Carr as Kathy, Page and Brooke Forsythe as Marcia and Norma Jean, Peggy Lipton, as Joanna, Tracy Stratford as Susan, and Sara Ballantine as Janice.

NBC advertising in February, 1965, gave a working title of The Mr. and The Misses.

When the format changed to espionage, it was explained to viewers that Major Foster had been recalled to active duty as a secret agent. All the other regulars except Forsythe and Marks were dropped from the cast. Peter Kortner was the producer of the series, which aired twenty-nine episodes from September 13, 1965, to August 29, 1966. The series was produced by Forsythe's own company in conjunction with Universal Television Studios. Earl Bellamy was the director.