Don Rickles was born in the New York City borough of Queens to Jewish parents Max and Etta Rickles. He grew up in the borough's Jackson Heights neighborhood. After graduating from Newtown High School, he served in the U.S. Navy in World War II aboard the USS Cyrene as a S1/c until he was honorably discharged in 1946. Two years later he studied at the American Academy of Dramatic Arts, and played occasional bit parts on television. Frustrated with the lack of acting work, he began doing stand-up comedy. He eventually became known as an insult comedian by learning to respond to hecklers. The audience liked these insults more than his prepared material, so he developed them as part of his act. His act reminded some observers of the older insult comic Jack E. Leonard, though Rickles has denied that Leonard had any influence on his style.

Rickles continues to be very active on the stand up comedy scene to this day. He is still a popular performer in Las Vegas and has many dates booked through the end of 2008. He has no plans to retire as he recently said in an interview: "I'm in good health. I'm working better than I ever have. The audiences are great. Why should I retire? I'm like a fighter. The bell rings and you come out and fight. My energy comes alive. And I still enjoy it."

In February 2007, Rickles made a cameo appearance (as himself) in a strange, recurring dream sequence that was woven through an episode (titled "Sub Conscious") of the CBS dramatic series, The Unit.

Rickles' memoir, Rickles' Book, was released on May 8, 2007 by Simon & Schuster. Mr. Warmth: The Don Rickles Project, a documentary about Rickles directed by John Landis, made its debut on HBO on December 2, 2007.

Rickles and his wife Barbara are close friends with comedian Bob Newhart and his wife, Ginny, and they often vacation together. Rickles and Newhart appeared together on The Tonight Show with Jay Leno on January 24, 2005, the Monday following Johnny Carson's death, reminiscing about their many guest appearances on Carson's show, including footage of the "cigarette box incident".

Rickles has been married for over 41 years to his wife, Barbara, who is from Philadelphia. They have a daughter, Mindy, a son, Larry and two grandchildren, Ethan and Harrison Mann. According to Rickles' memoir, his grandchildren are much more impressed by his having played "Mr. Potato Head" than by any of his other career achievements.