Most famous for creating the television sitcom The Beverly Hillbillies, he was also crucial in developing the "rural" comedies Petticoat Junction (1963–1970) and Green Acres (1965–1971) for CBS.

He produced the Ray Bolger Show, and wrote (or co-wrote) screenplays such as Lover Come Back (1961, for which he was nominated for an Oscar for Best Writing: original screenplay), and (with Stanley Shapiro) Bedtime Story (1964), which was re-made in 1988 as Dirty Rotten Scoundrels (Steve Martin, Michael Caine), and again in 2019, as The Hustle (Anne Hathaway, Rebel Wilson).

In 1962, Henning created the CBS series, The Beverly Hillbillies—a sitcom based on his past experiences while camping in the Ozarks near Branson, Missouri.

Thus, in 1971, The Beverly Hillbillies and Green Acres were canceled as a result of the "rural purge", joining Petticoat Junction (which ended the year before) in syndicated reruns.

Ruth Henning often told her husband about how her female cousins and she often visited her grandparents at the tiny hotel they owned near the Rock Island railroad station located in Eldon, Missouri.

Many details about Henning's personal life and career were recounted by Ruth in a 1994 manuscript that was discovered in archives and subsequently published in 2017.