Lewis was born in Chicago, Illinois on May 22, 1922, the youngest of three children. Her father, Leon, was a pianist, musical director for CBS, and composer while her mother, Jessica, was a singer with the Chicago Opera Company, with Lewis studying her voice with her mother. At the age of 11, Lewis' family moved to New York City due to The Great Depression.
Lewis began singing on radio after a successful audition with WMCA in New York City led to her own program. While studying at Hunter College at the age of seventeen, she started working as a singer for a radio show called Gloom Dodgers in order to support her family. Shortly after working for Gloom Dodgers, Lewis had a radio show titled Monica Makes Music. She went on to co-star on The Chesterfield Supper Club on radio.
She won a part as a singing cigarette girl in the Broadway show Johnny 2X4. Lewis' work on Broadway then led to her performing at the Stork Club and left school, changing her name from May to Monica because she thought it was "sexier", telling The New York Times that "I feel much more like Monica and I look much more like Monica, too".
In 1943, jazz pianist Leonard Feather told Lewis that bandleader Benny Goodman needed a singer since Peggy Lee had left upon marrying his band's guitarist, Dave Barbour. At an audition in Times Square with hundreds of women participating, Lewis earned the part as a singer and began to sing on Hotel Astor's roof with Goodman's orchestra. With the help of Goodman she began to establish her career through nationally broadcast shows such as The Revere Camera Show and Beat the Band. Lewis was dubbed "America’s Singing Sweetheart" during this time. Some of her songs included "Put the Blame on Mame", "I Wish You Love", and "Autumn Leaves." However, Lewis' parents did not allow her to perform in out-of-town tours.
For a short time, Lewis participated in advertisements for companies such as Burlington Mills and Camel cigarettes.
In 1947, Lewis began to provide the singing voice for "Miss Chiquita Banana", a cartoon television commercial character. In 1948 she appeared in the first ever Ed Sullivan Show, which was created and produced by her brother Marlo Lewis.
In 1950, she was signed to a contract with MGM. Some of her films included The Strip, Everything I Have Is Yours, and Affair with a Stranger, and she later appeared in some 1970s disaster films such as Earthquake (1974), Rollercoaster (1977), and both Airport '77 (1977) and The Concorde ... Airport '79 (1979).
She also from the 1950s to the 1980s made appearances in several television action series, including Peter Gunn, Johnny Staccato, The Virginian and Ironside.
She spoke about her career just 10 days before her death to The New Yorker magazine, in an article published in the September 7, 2015 edition
Lewis was married twice. Her first husband was the American record producer Bob Thiele. They married in 1945 but divorced a couple of years later. She moved to Beverly Hills, California in the 1950s. In 1956, she married film producer Jennings Lang and they remained together until his death in 1996. They had three children. Her sister Barbara was a pianist and her brother Marlo worked as a television producer.
In her 2011 memoir Hollywood Through My Eyes, Lewis revealed that actor (and future U.S. President) Ronald Reagan had proposed to her. However, Lewis declined Reagan's marriage proposal.
Monica Lewis died of natural causes at the age of 93 on June 12, 2015 at her home in Woodland Hills, California.