In 1947 she played her first leading role in Slave Girl and then in
1949 had her biggest success. As the female lead opposite Burt
Lancaster in Criss Cross, she played a femme fatale, and her career
began to ascend. The 1957 film Band of Angels featured her opposite
Clark Gable in an American Civil War story, along with Sidney Poitier
and Efrem Zimbalist, Jr.
However, her most famous role that led her to pop culture legacy is of Lily Munster in the cult television series The Munsters (1964-1966), which allowed De Carlo to demonstrate a comic flair that her films had failed to utilize. She also played Lily in the 1966 feature film Munster, Go Home and the 1981 TV movie The Munsters' Revenge
For the next several years, she was constantly working although many of the films failed to advance her career.
Cast in The Ten Commandments (1956) in a leading role (as Zipporah, also spelled Sephora, Moses' wife), De Carlo was part of a major hit. The film was a huge success and De Carlo was among those to be praised for her restrained work.