Since acting was not a major study at the university, he left and enrolled at the Pasadena Community Playhouse, where he won a scholarship and stayed for three years.

By the early 1940s, he was appearing regularly in films such as: The Male Animal (1942), A Guy Named Joe (1943), Thirty Seconds Over Tokyo (1944), You Came Along (1945), Without Reservations (1946), It Happened on 5th Avenue (1947), Romance on the High Seas (1948), My Friend Irma (1949), and Jumping Jacks (1952).

Beginning in 1952, DeFore had a recurring role as the Nelsons' friendly neighbor, "Thorny", on the ABC sitcom The Adventures of Ozzie and Harriet,[10] earning a nomination in 1955 for a Best Supporting Actor in a Regular Series Primetime Emmy Award.

[11] In time, though, the role of Thorny was superseded by Lyle Talbot as Joe Randolph, and Mary Jane Croft as his wife Clara.

[13] In 1970, DeFore appeared as Mayor Evans on the TV Western The Men from Shiloh in the episode titled "Colonel Mackenzie Versus the West".

[16] DeFore and his family were longtime residents of the Mandeville Canyon section of Brentwood and attended the Village Church of Westwood Lutheran.

[19] From 1957 to 1962, DeFore and his family operated the Silver Banjo Barbecue, a restaurant located in Frontierland of Disneyland Park in Anaheim, California.

[20] His friend, former actor and 40th President of the United States Ronald Reagan, appointed him to the Presidential Advisory Council to the Peace Corps.

[21] His youngest son, Ron, also held political positions within the Reagan Administration, which he highlights in his book, Growing Up in Disneyland, Waldorf Publishing, 2019, that was both an autobiography and partial biography of his father.

On December 22, 1993, DeFore died of cardiac arrest at Saint John's Health Center in Santa Monica, California.