He was born in New York City, New York as Francis Xavier Aloysius James Jeremiah Keenan Wynn, the son of Jewish American vaudeville comedian Ed Wynn, and his Irish-American Catholic wife, the former Hilda Keenan, but took his stage name from his maternal grandfather, Frank Keenan, one of the first Broadway actors to star in Hollywood.

Keenan Wynn became an actor with Ed Wynn's encouragement and the two appeared together in the original Playhouse 90 television production of Rod Serling's Requiem for a Heavyweight. The son was returning the favour: according to radio historian Elizabeth McLeod, it was Keenan who had helped his father overcome professional collapse and a harrowing divorce and nervous breakdown to return to work a decade earlier, and who now helped convince Serling and producer Martin Manulis that the elder Wynn should play the wistful trainer. as well as a subsequent TV drama detailing the problems they'd experienced while working on that show called The Man in the Funny Suit. In that show, the Wynns, Serling and much of the cast and crew played themselves. Keenan was also in another of Rod Serling's productions, an episode of The Twilight Zone entitled "A World of His Own".

Keenan Wynn appeared in hundreds of movies and television shows between 1934 and 1986. His credits include The Clock, Royal Wedding, Alias Smith and Jones, Emergency!, Annie Get Your Gun, Kiss Me, Kate, The Man in the Gray Flannel Suit, Dr. Strangelove or: How I Learned to Stop Worrying and Love the Bomb, The Absent-Minded Professor, Son of Flubber, and Herbie Rides Again.

In the 1959-1960 television season, Wynn co-starred with Bob Mathias in NBC's The Troubleshooters, an adventure program centered about unusual events regarding an international construction company. Wynn played the role of Kodiak, the "troubleshooter," to Mathias's Frank Dugan.

Wynn took a dramatic turn as Yost in the crime drama Point Blank with Lee Marvin. He played Hezakiah in the 1965 comedy The Great Race. He was the voice of the Winter Warlock in the holiday classic Santa Claus Is Comin' to Town and was in several Disney films, including Snowball Express and The Shaggy D.A.. He had an uncredited role in Touch of Evil.

He appeared in Francis Coppola's musical Finian's Rainbow, Sergio Leone's epic western Once Upon a Time in the West, and Robert Altman's critically acclaimed Nashville.

Wynn became a regular on TV's Dallas from 1979–81, playing the part of former Ewing family partner-turned-enemy Willard "Digger" Barnes. The role was originally played in the first season by fellow character actor and friend David Wayne.

Wynn was initially cast to play Perry White (Clark Kent and Lois Lane's boss at the Daily Planet) in 1978's Superman: The Movie in April 1977. However, by June (as production moved to Pinewood Studios in England), Wynn collapsed from extreme exhaustion and was rushed to the hospital. He was ultimately replaced by Jackie Cooper.

In his later years, Wynn undertook a number of philanthropic endeavors and supported several charity groups. He was an active member of the Westwood Sertoma service club, in West Los Angeles, for many years. In 1984 he starred in the television movie Call to Glory, which later became a weekly television series.

During the series, his co-stars were aware that he was suffering from pancreatic cancer, which claimed him in 1986 at age 70. He is buried in Glendale's Forest Lawn Memorial Park.