In December of 1940 Darryl F. Zanuck, President of 20th Century Fox, signed Carole to a seven year contract at the studio. The press predicted that he was going to make her a big star like he had done for Betty Grable and Alice Faye. Zanuck said "I figured any girl who is so popular with men, whom so many men want to date, must have something we can use and need in our pictures." Director Rouben Mamoulian offered Carole a role in his big budget drama Blood and Sand. When she turned it down rumors began that she didn't want to dye her hair red. It's more likely that she turned it down because Zanuck had promised her the lead in the Western Belle Starr. Carole was devastated when he gave that role to Gene Tierney instead. Her first assignment at Fox was a supporting role the technicolor musical Moon Over Miami. Then she got the chance to show off her singing voice in the musicals Dance Hall and Cadet Girl. In 1942 she was given leading roles in A Gentlemen At Heart, It Happened In Flatbush, and Manila Calling.

She said "The busier they keep me the better I like it. I've been fighting to get up on this ladder for five years ever since I ran away from high school." Unfortunately Darryl Zanuck had a reputation as a sexual predator who slept with all the actresses at Fox. Carole did have a sexual relationship with him and gossip about their affair hurt her reputation in Hollywood. When she stopped giving in to Zanuck's sexual demands he was furious. She had signed on to star in Highway To Hell with Cesar Romero but the movie was abruptly cancelled. Then she was supposed to play the lead in the technicolor musical My Gal Sal. Right before filming began Zanuck hired Rita Hayworth to play the lead and recast Carole in a supporting role. She was so upset that she begged her fans to write to Fox and ask them to cast her in better movies. Zanuck was upset when Carole took five months off to go on a USO tour. When she returned from the trip he punished her with a minor role Wintertime.
During her time at Fox Carole was often loaned out to other studios. She made The Powers Girl at United Artists and Having Wonderful Crime at RKO. Despite Zanuck's efforts to sabotage her career she was very popular at the studio. Directors like Ray McCarey loved working with her and she always got along with the crew. She was happy when Fox agreed to make her book Four Jills In Jeep into a movie. However she had no creative control over the script and it ended up being a disappointment. By 1945 she was earning $1350 a week but she was unhappy with the films she was being offered. She turned down leading roles in The Spider and Doll Face because she felt they were inferior projects. Carole begged Zanuck to let her make a screen test for the comedy Cluny Brown but was told she was "too glamorous" to play the part. Instead she was cast in the low budget drama Behind Green Lights. She hated the script and would later say it was her least favorite role. Carole really wanted to play the lead in Forever Amber but her friend Linda Darnell got the role.
Outside her studio dressing room
When she was assigned a bit part in Somewhere In The Night she refused to do it. She said "it would be detrimental to my career." Zanuck immediately put her on suspension without pay. After returning to the studio she made the comedy It Shouldn't Happen To A Dog. It would be her last movie at Fox. On October 24, 1946 she found out that her contract would not be renewed. Carole was so devastated that she attempted suicide and was hospitalized. Later she said she was glad her days at Fox were over because "my last pictures on the lot were pretty dreary." She had worked at 20th Century Fox for six years and despite some success she never became an A-list star. After Carole's death Darryl Zanuck spread lies that she was a bad actress and that she "slept with everyone" at the studio. He cruelly nicknamed her "the studio hooker." Unfortunately these lies hurt Carole's legacy and many film historians dismissed her as an untalented B-actress.