Nita Naldi was asked to perform in a short film with Scottish comedian Johnny Dooley (no relation). She quit the film after realizing that Dooley had romantic intentions with another woman. She was then offered a role in A Divorce of Convenience with Owen Moore. After those two films, she had small roles in several independent films before being selected for Dr. Jekyll and Mr. Hyde with John Barrymore. The role in the film would give Naldi much prestige. During the production of Dr. Jekyll and Mr. Hyde, Barrymore and Naldi became friends, and stayed friends for many years, with Barrymore lovingly calling her the Dumb Duse. Nita Naldi was selected by Spanish author Vicente Blasco Ibáñez for the role of Dona Sol in film version of his novel, Blood and Sand (1922). Naldi was signed by Famous Players-Lasky for the role, and it became her first pairing with screen idol Rudolph Valentino; the film was a major success, for it gave Naldi the image of a vamp, which would follow her for the rest of her life. Naldi and Valentino were never romantic, and she would be one of the few to befriend his wife Natacha Rambova though that friendship would sour when the Valentinos divorced. During this time, she posed for famous pin-up artist Alberto Vargas, who painted Naldi topless next to the bust of a satyr. While Valentino went on his one-man strike, which prevented him from appearing on film, Naldi took on several Famous Players-Lasky roles with growing importance including The Ten Commandments (1923), directed by Cecil B. DeMille. When Valentino returned and fixed his contract woes, she joined him for his final Famous Players-Lasky film, the now lost A Sainted Devil (1924). Naldi left the company soon after.
In 1924 the Valentinos and Nita Naldi traveled to France in order to do research for the film The Hooded Falcon which was never made. Upon returning to California, the duo made Cobra. The film was not well received, and Cobra became the last film that both Naldi and Valentino starred together. The Valentinos’ marriage was ending around this time. After Valentino signed a contract with United Artists, he banned Rambova from the set. She was given her own film as a consolation. Naldi starred in Rambova’s production What Price Beauty? (1925). The film suffered distribution problems, was barely noted at the time, but is noteworthy for being actress Myrna Loy’s first screen appearance. After finishing the Dorothy Gish film Clothes Make the Pirate, Naldi left for France for a short vacation, where she married J. Searle Barclay during this time. Despite multiple rumors that she had retired, Naldi began work on several films, including Alfred Hitchcock’s second directorial effort, 1926’s The Mountain Eagle. She is often mistakenly credited for appearing in Hitchcock’s The Pleasure Garden. Naldi made two films in France and one in Italy before retiring. Despite having an acceptable voice, Naldi never made a talkie.

Due to the financial reversals caused by her retirement from films, as well as the Depression, Nita Naldi filed bankruptcy in 1932. She went back to the stage with Queer People and The Firebird in 1933. The press had been critical of her weight since 1924, but reviews to her appearances in both plays were especially harsh this time around—so harsh in fact that Naldi filed suit against one paper in 1934 for $500,000. The suit was dismissed in 1938. In 1942, Naldi was considered for For Whom the Bell Tolls but did not receive the part. She never made another film. That same year she began appearing in a revue in New York with Mae Murray reciting the 1897 poem “A Fool There Was” in full kitsch. In 1952, she had a notable role in the play In Any Language, co-starring the legendary stage actress Uta Hagen. In 1955, she coached Carol Channing how to vamp, for Channing’s new musical The Vamp. Channing would be nominated for Best Actress in a Musical for that role. Naldi spent her final years in New York City. where she died of a heart attack in her apartment little over three months after her 66th birthday. She was buried in the family plot at Calvary Cemetery in Queens, New York. For her contribution to the film industry, Nita Naldi was honored with a star on the Hollywood Walk of Fame at 6316 Hollywood Blvd.