Reiner was born in the Bronx, New York on March 20, 1922, the son of Irving, who was a watchmaker, and Bessie (née Mathias) Reiner. His parents were Jewish immigrants, his father from Romania and his mother from Austria. When he was sixteen, his older brother Charlie read in the New York Daily News about a free dramatic workshop being put on by the Works Progress Administration and told him about it. His uncle, Harry Mathias, was the first entertainer in his family. He had been working as a machinist repairing sewing machines. He credits Charlie with changing his career plans.
Starting in 1960, on The Steve Allen Show, Reiner teamed with Mel Brooks as a comedy duo. Their performances on stage and television included Reiner playing the straight man to Brooks' 2000 Year Old Man character. The routine eventually expanded into a series of five comedy albums and a 1975 animated TV special.
In 1959, Reiner developed a television pilot, Head of the Family, based on his own personal and professional life. However, the network didn't like Reiner in the lead role. In 1961, it was recast and retitled The Dick Van Dyke Show, and became an iconic series, making stars of his lead actors Dick Van Dyke and Mary Tyler Moore. In addition to writing many of the episodes, Reiner occasionally appeared as temperamental show host "Alan Brady", who ruthlessly browbeats his brother-in-law (played by Richard Deacon). The show ran from 1961 to 1966. In 1966, he co-starred in the Norman Jewison film The Russians Are Coming, The Russians Are Coming.
Reiner began his directing career on the Van Dyke show. After that show ended its run, Reiner's first film feature was an adaptation of Joseph Stein's play Enter Laughing (1967), which in turn was based on Reiner's semi-autobiographical 1958 novel of the same name. Balancing writing, directing, producing, and acting, Reiner has worked on a wide range of films and television programs. Films from his early directing career included the cult comedy Where's Poppa? (1970), starring George Segal and Ruth Gordon, Oh, God! (1977) with George Burns and The Jerk (1979) with Steve Martin.
Reiner is the author of several books, including his 2004 memoir, My Anecdotal Life: A Memoir, and novels such as 2006's NNNNN: A Novel. In American Film, Reiner expressed his philosophy on writing comedy: "You have to imagine yourself as not somebody very special but somebody very ordinary. If you imagine yourself as somebody really normal and if it makes you laugh, it's going to make everybody laugh. If you think of yourself as something very special, you'll end up a pedant and a bore. If you start thinking about what's funny, you won't be funny, actually. It's like walking. How do you walk? If you start thinking about it, you'll trip."
In May 2009, he guest-starred as a clinic patient on the season finale of House. Reiner also lent his voice to the character of Santa Claus in the NBC Christmas special Merry Madagascar in November 2009 and reprised his role as Santa in The Penguins of Madagascar holiday special "The All Nighter Before Christmas. In December 2009, Reiner guest-starred as a television producer on the CBS sitcom Two and a Half Men. In June 2010, Reiner guest starred in TV Land's new series "Hot in Cleveland" as Elka Ostrovsky's date and reprised the role in July 2010. Reiner also made appearances on The Cleveland Show as Murray and wrote the story for the episode "Your Show of Shows", named after the program that started his career.
On December 24, 1943, Reiner married singer Estelle Lebost. The two were married 64 years until her death in 2008. At the time of the marriage, Reiner was 21 and she was 29. Estelle delivered the line "I'll have what she's having" in the deli scene of their son Rob's 1989 film When Harry Met Sally. She died on October 25, 2008, at age 94.