Chaykin was born in Brooklyn, New York. His father, Irving J. Chaykin (1912–2007), was born in Brooklyn, and was a professor of accountancy at City College of New York. His mother, Clarice Chaykin (née Bloomfield, 1921–2012), was born in Winnipeg, Manitoba, but raised in Montreal, Quebec since the age of three. She graduated from Beth Israel Hospital nursing school in Newark, New Jersey. Chaykin's maternal uncle, George Bloomfield (1930–2011), was a veteran Canadian Director, Producer, Writer and actor who directed Chaykin in a number of projects for film and television.

Two of Chaykin's early motion picture roles brought him public recognition: computer programmer Jim Sting in WarGames and prosecution witness Sam Tipton in My Cousin Vinny. In 1990, he had a small but pivotal role in the film Dances with Wolves, portraying Major Fambrough.

Chaykin had his first starring role in Whale Music, a 1994 film in which he played a burned-out rock star, a character based largely on Brian Wilson. Chaykin was named Best Actor at the 15th Genie Awards for his portrayal.

Chaykin was known for portrayals of blustery supporting characters. One of his rare leading roles was Nero Wolfe. Chaykin first played the legendary detective in The Golden Spiders: A Nero Wolfe Mystery (2000), an A&E telefilm adaptation of the 1953 novel by Rex Stout. Timothy Hutton costarred in the production as Archie Goodwin. The New York Times reported Chaykin's "undisguised delight" at starring in the promotion for The Golden Spiders: "There's an extraordinary billboard up on Sunset Boulevard right now, with a humongous photograph of my face. ... I drive by it constantly, back and forth, back and forth." The original movie's success led to the weekly series, A Nero Wolfe Mystery, which played for two seasons on A&E and continues to air internationally. Chaykin and Hutton had worked together previously, albeit briefly, in the 1985 film Turk 182; and they worked together subsequently, in the 2006 film Heavens Fall.

Raised in New York City, Chaykin studied drama at the University at Buffalo, The State University of New York. He subsequently moved to Toronto, Ontario, where he resided until his death. Chaykin's first marriage, to Canadian Producer Ilana Frank, ended in divorce. He was subsequently married to Canadian Actress Susannah Hoffmann, with whom he had one daughter, Rose. Best known for having played Jen Pringle in the Anne of Avonlea series, Hoffmann had a supporting role in a 2002 episode of the television series A Nero Wolfe Mystery, in which Chaykin starred.

Chaykin portrayed the colourful bookie Frank Perlin opposite Philip Seymour Hoffman's compulsive gambler Dan Mahowny in Owning Mahowny, a film that critic Roger Ebert named as one of the ten best of 2003. In 2006, Chaykin appeared in an episode of the Ken Finkleman miniseries At the Hotel and received a Gemini Award for best performance by an actor in a guest role. He had a semi-recurring role in the HBO series Entourage, as volatile movie Producer Harvey Weingard, a send-up of the celebrated Producer Harvey Weinstein. He also appeared as Stan Deane, father of Kevin Zegers' character Woody Deane, in the 2006 romantic comedy It's a Boy Girl Thing.

Chaykin starred as Sam Blecher, the owner of a family-run driving school in Winnipeg, in the first two seasons (2008–2010) of the Canadian comedy-drama television series Less Than Kind. The series received the 2010 Gemini Award for Best Comedy Program or Series.

Maury Chaykin died in Toronto on July 27, 2010, his 61st birthday, from complications of a heart valve infection.

In 2011 Chaykin posthumously received the ACTRA Toronto Award for Outstanding Performance — Male for his performance as Sam Blecher in Less Than Kind. He had been nominated for the award in 2003, for his portrayal of Nero Wolfe.