When DeSylva became a producer at Paramount Pictures, Hutton was signed to a featured role in The Fleet's In which starred Dorothy Lamour in 1942. Hutton made an instant impact with the moviegoing public but Paramount did not immediately promote her to major stardom, giving her second leads in a Mary Martin musical and another Lamour film before casting Betty as Bob Hope's leading lady in Let's Face it in 1943. Following the release of The Miracle of Morgan's Creek (1944), Betty was indisputably a major star and with the release of 1945's Incendiary Blonde, Hutton had supplanted Lamour as Paramount's number one female box office attraction.
Hutton made 19 films in 11 years, from 1942 to 1952 including a hugely popular The Perils of Pauline in 1947. She was billed over Fred Astaire in the 1950 musical Let's Dance. Hutton's greatest screen triumph was Annie Get Your Gun for MGM, which hired Hutton to replace an exhausted Judy Garland in the role of Annie Oakley. The film and the leading role, retooled for Hutton, was a smash hit, with the biggest critical praise going to Betty (her obituary in The New York Times described her as "a brassy, energetic performer with a voice that could sound like a fire alarm") but Hutton, like Garland, was earning a reputation for being extremely difficult.
In 1944, she signed with Capitol Records, one of the first artists to do so, but was unhappy with their management, and later signed with RCA Victor. Among her many films was a unbilled cameo in Sailor Beware (1952) with Dean Martin and Jerry Lewis, in which she portrayed Jerry's girlfriend, Hetty Button. Her time as a Hollywood star came to an end due to contract disagreements with Paramount following The Greatest Show on Earth (1952) and Somebody Loves Me (1952), a biopic of singer Blossom Seeley. The New York Times indicated that her film career ended because of her insistence that her husband at the time, Charles O'Curran, direct her next film; when the studio declined, Hutton broke her contract.
Hutton worked in radio, appeared in Las Vegas and in nightclubs, then tried her luck on the new medium of television. An original musical TV "spectacular" written especially for Hutton, Satin 'n Spurs (1954), was an enormous flop with the public and critics, despite being one of the first television programs televised nationally by NBC in compatible color. Desilu Productions took a chance on Hutton and in 1959 gave her a sitcom The Betty Hutton Show, which quickly faded. Her last TV outing was a brief guest appearance in 1975 on Baretta.
In 1967, she was signed to star in two low-budget Westerns for Paramount, but was fired shortly after the projects began. Afterwards, Hutton had trouble with alcohol and substance abuse, eventually attempting suicide after losing her singing voice in 1970 and having a nervous breakdown. She divorced her fourth husband, jazz trumpeter Pete Candoli, and declared herself bankrupt. However, after regaining control of her life through a church, she converted to Roman Catholicism and went on to teach acting and to cook at a rectory in Rhode Island.
On Broadway, she temporarily replaced a hospitalized Carol Burnett in Fade Out - Fade In in 1964 and followed Dorothy Loudon as the evil Miss Hannigan in Annie in 1980. Her last known performance in any medium was on Jukebox Saturday Night, which aired on PBS in 1983. Robert Osborne interviewed her for TCM's Private Screenings in April 2000; the interview first aired on JUly 18, 2000. The program was rerun as a memorial on the evening of her death.