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Reiner was born in New York City to Estelle and Carl Reiner, who were themselves actors. Reiner began his career as an actor before transitioning to filmmaking. He rose to prominence with his portrayal of Michael "Meathead" Stivic on the CBS television sitcom All in the Family (1971–1979), a role that earned him two Primetime Emmy Awards for Outstanding Supporting Actor in a Comedy Series.

He directed a string of critically acclaimed films starting with the heavy metal mockumentary This Is Spinal Tap (1984), followed by the romantic road comedy The Sure Thing (1985), the coming-of age drama Stand by Me (1986), the adventure romance The Princess Bride (1987), the romantic comedy When Harry Met Sally... (1989), the psychological thriller Misery (1990), the legal drama A Few Good Men (1992), which was nominated for the Academy Award for Best Picture, and the political romance The American President (1995). He acted in films such as Sleepless in Seattle (1993), Bullets Over Broadway (1994), The First Wives Club (1996), Primary Colors (1998), EDtv (1999), and The Wolf of Wall Street (2013). He also co-founded the production company Castle Rock Entertainment in 1987.

Reiner was also a liberal political activist who advocated for causes such as LGBTQ rights, early childhood education, and environmental protection, and who campaigned for a variety of Democratic candidates. Reiner chaired the 1998 campaign to pass California's First 5 childhood education initiative, and in 2008 he and his wife, Michele, co-founded the American Foundation for Equal Rights, which initiated the court challenge against California's same-sex marriage ban.

On December 14, 2025, Reiner and his wife were found stabbed to death in their Los Angeles home. Their son, Nick Reiner, has been charged with two counts of first-degree murder.