Born in 1911, he grew up in a large Jewish immigrant family in Brooklyn, New York. He graduated from Brooklyn College in 1934. He married Esther Levine (1910-1999) and had two children, Emily and Conrad, the latter a graduate of Columbia University, an architect, a resident of New York City, and father of four children.
In 1956 he hosted the game show Two for the Money, having replaced fellow humorist Herb Shriner. From 1959 to 1964, he hosted The Sam Levenson Show. Over a span of more than a decade, he appeared on Toast of the Town aka The Ed Sullivan Show twenty-one times, in addition to frequently serving as a substitute host on CBS's Arthur Godfrey Time. He was a guest host on The Price Is Right and was a panelist on many other television programs such as Password and What's My Line? Levenson also had a cameo in the film A Face in the Crowd. Levenson also appeared multiple times on The Tonight Show Starring Johnny Carson through the 1970s. Levenson wrote the well-known poem "Time Tested Beauty Tips" for his grandchild, which has become falsely attributed to Audrey Hepburn.
Levenson was originally a Spanish teacher at Samuel J. Tilden High School in Brooklyn, New York. He was an author and wrote Everything But Money (1966), the bestseller Sex and the Single Child (1969), In One Era And Out The Other (1973), You Can Say That Again, Sam! (1975), and You Don't Have to be in Who's Who to Know What's What (1979). Levenson appeared frequently in the "Borscht Belt" hotels of the Catskill Mountains.
The 150-seat Sam Levenson Recital Hall at Brooklyn College was named after him in 1988 in gratitude for his donations over the years to the Performing Arts Center. A glazed porcelain bust of him graces the hall's rear wall. The library of Franklin K. Lane High School, from which he graduated in 1930, is named for him, and a large portrait painting of him hangs on the north wall of the library. During Lane High School's rededication ceremony in the fall of 1976, Levenson was an honored guest and gave a humorous speech about his days as a student.
One of his brothers was the WPA muralist and artist, teacher, and art critic Michael Lenson.