He then gained acclaim in his television career for his portrayal of cartoonist John Monroe in the short-lived NBC sitcom My World and Welcome to It (1969–1970), winning him the Primetime Emmy Award for Outstanding Lead Actor in a Comedy Series.

before gaining acclaim for his recurring role on the CBS mystery series Murder, She Wrote (1986-1996), portraying Dr. Seth Hazlitt of Cabot Cove opposite Angela Lansbury.

Windom is also known for his film roles in the Academy Award-winning movie To Kill a Mockingbird (1962), The Americanization of Emily (1964), The Detective (1968), Brewster McCloud (1970), Escape from the Planet of the Apes (1971), Planes, Trains and Automobiles (1987), She's Having a Baby (1988), Uncle Buck (1989), Miracle on 34th Street (1994), and True Crime (1999).

He participated in the Army Specialized Training Program, studying at The Citadel, Antioch College, and the University of Kentucky.

While stationed in Frankfurt during the Allied occupation of Germany, he enrolled in Biarritz American University in France and became involved in theater.

He continued guest-starring in series during the 1960s including playing The Major in "Five Characters in Search of an Exit", a 1961 episode of The Twilight Zone; Windom considered this guest appearance as his West Coast television debut.

His first leading role came in the sitcom The Farmer's Daughter (1963–1966), a series based on the 1947 film about a young Minnesota woman (played by Inger Stevens) who became the housekeeper for a widowed congressman (Windom).

Windom's first role in film was alongside Gregory Peck in the Oscar-winning movie To Kill a Mockingbird (1962); he played Horace Gilmer, the prosecutor of Tom Robinson (Brock Peters).

He appeared on The Donna Reed Show, Gunsmoke, Star Trek, Mission: Impossible (four episodes), and Ironside.

In 1971 he played a supporting role alongside Jimmy Stewart, George Kennedy, and Kurt Russell in the Columbia production Fools' Parade.

Windom starred with Frank Sinatra in the film The Detective (1968), playing a homophobic killer, a role appreciated in The New York Times.

In 1975, he guest-starred as George Kane, a desperate drug dealer, in the series finale of Mannix in the episode "Hardball".

Windom briefly left the show in 1990 to work on the first television version of Parenthood, based on the 1989 film of the same name, playing the role of patriarch Frank Buckman--a role played by Jason Robards in the film and, later, Craig T. Nelson in the second TV version.

[4] In 1974, Windom met Patricia (Fehrle) Tunder while shooting a TV movie; 12 years his junior, she was working for the production company at the time.