"My grandmother was a Jewish juggler: she used to worry about six things at once." -Richard Lewis

Lewis was raised in Englewood, New Jersey, the son of Blanche, an actress, and William Lewis, a caterer. He graduated from Dwight Morrow High School and received a degree from Ohio State University, where he was a member of the Alpha Epsilon Pi fraternity. As a teenager, Lewis appeared on the Candid Camera television show.

Lewis began performing stand-up comedy in the 1970s. He worked as a copywriter for an ad agency by day, while honing his stand-up act at night. The ad agency was named Contemporary Graphics (no longer exists) and was located above Lovey's pizzeria in Hasbrouck Heights, New Jersey. Lewis gained popularity in the 1980s with numerous appearances on Late Night with David Letterman and his own television specials on HBO. He has starred in the ABC sitcom Anything But Love which ran for four seasons. He had a recurring role on Showtime series Rude Awakening and as a rabbi on the dramatic series 7th Heaven. Lewis has written comic articles for magazines such as Playboy, and endorsed the popular early-1990s beverage, Boku, as well as Snapple.

He currently has a frequent recurring role as himself on Larry David's critically acclaimed Curb Your Enthusiasm on HBO. Lewis and David met at summer camp in Cornwall-on-Hudson, New York when they were thirteen.

Lewis has also achieved moderate success in films, appearing as Prince John in Robin Hood: Men in Tights and as a frontier doctor in Wagons East!. He appeared in the dramatic films Leaving Las Vegas and Drunks. He made his acting debut in the 1977 TV movie mockumentary Diary of a Young Comic.

Lewis claims to be the originator of the expression "the ______ from hell" as in "the date from hell" or "the roommate from hell". This theory is expounded in the Curb Your Enthusiasm episode "The Nanny from Hell". Lewis has petitioned the editors of Bartlett's to be given credit for the coinage, but the editors claim that the phrase was a common idiom prior to Lewis' use of it. However, the Yale Book of Quotations does attribute the phrase to Lewis.

Lewis returned to the Howard Stern Show on February 14th, 2008, where he discussed his alcoholism and addictions. Throughout this appearance, he and Stern staff-member Artie Lange good-naturedly teased each other. Near the end of his segment, Artie admitted that Lewis' Showtime specials in the 1980's were what inspired him to become a stand-up comedian; Richard, however, reacted uncomfortably to this praise.