Born Phyllis Kirkegaard in Syracuse, New York (some sources state Plainfield, New Jersey), she contracted polio as a child which resulted in health problems for the rest of her life. As a teen, she moved to New York City to study acting and changed her last name to "Kirk". She began her career on Broadway before embarking on a television and film career.

Kirk is best known for her many roles throughout the 1950s. She appeared with Vincent Price in the 3-D horror film House of Wax in 1953. Her most notable television role was opposite Peter Lawford in The Thin Man (1957—1959), where they played Nick and Nora Charles. She also appeared with Jerry Lewis in his 1957 film The Sad Sack, with Robert Ryan, Anita Ekberg, and Rod Steiger in the 1956 film Back from Eternity. Kirk was a regular on The Red Buttons Show and appeared as a guest on some television programs, including an episode of The Twilight Zone : A World of His own.

As her acting career slowed down, Kirk began serving as an activist for various social causes. She vocally opposed Death row inmate Caryl Chessman's death sentence and visited Chessman in prison until his execution in 1960. After the Watts Riots in 1965, she funded preschool programs for underprivileged families South Los Angeles. She also granted interviews and wrote for the American Civil Liberties Union newspaper. Kirk made her last onscreen appearance in a 1970 episode of The F.B.I. before leaving show business altogether to enter public relations. She worked as a publicist for CBS News, retiring in 1992.

Kirk was married to television producer and screenwriter Warren Bush until his death in 1992.

Kirk died on October 19, 2006 of a post-cerebral aneurysm at age 79 in Woodland Hills, California. She was buried with her husband Warren Bush in the Arlington National Cemetery in Virginia.