Windom was born in New York City, the son of Isobel Wells (née Peckham) and Paul Windom, an Architect. He was the great-grandson of the United States Secretary of the Treasury of the same name. He attended Williams College before enlisting in the army. He served in the United States Army in the European Theater of Operations in World War II, as a paratrooper with Company B, 1st Battalion 508th Parachute Infantry Regiment, 82nd Airborne Division.
Windom appeared in 1961 "All Is Forgiven" episode of The Donna Reed Show as 'Ed Corwin' and the 1962 episode 'Wide Open Spaces" as 'David Adams'.
Windom's first motion picture role was as Mr. Gilmer, the prosecutor of Tom Robinson in the 1962 Academy Award-winning To Kill a Mockingbird.
From September 1963 to April 1966, he co-starred in the television version of the previous film, The Farmer's Daughter, a series about a young Minnesota woman who becomes the housekeeper for a widowed congressman. In the 1969–1970 NBC series My World and Welcome to It, Windom played the James Thurberesque lead and received an Emmy Award for Outstanding Continued Performance by an Actor in a Leading Role in a Comedy Series. After the cancellation of the series, Windom toured the country for a time in a one-man Thurber show. After the run was completed, Windom filmed the pilot for a new series Is There a Doctor in the House? with Rosemary Forsyth. The pilot was written with both actors in mind for the two starring roles, and while it was well received by the critics and in viewership ratings in both its first run and a rerun in the summer of 1971, it was not picked up for a series.
In 1968, he starred with Frank Sinatra in The Detective, playing a homophobic killer. The role received great reviews from The New York Times.
He was a regular for a decade on the series Murder, She Wrote with Angela Lansbury. His initial appearance in the role was in October 1985. (He had previously appeared as a guest star playing another character in April 1985.) The producers enjoyed his work, and consequently invited him to return at the beginning of the second season to take on the role permanently. He briefly left the show to work on the first television version of Parenthood in 1990, playing the role of patriarch Frank Buckman (played by Jason Robards in the movie and Craig T. Nelson in the second TV version). But the show was short-lived (canceled after 12 episodes) and Windom returned to Murder, She Wrote as a semi-regular for the remainder of the run of that series.
He died on August 16, 2012, at the age of 88 at his home in Woodacre, California from congestive heart failure. He was survived by four of his children – Rachel, Heather, Hope and Rebel – and four grandchildren.
