After an affair while they were both married to other people, Loden married film Director Elia Kazan, who was twenty-three years her senior. Though the couple had become estranged and had previously considered divorce, they were still married at the time of her death from breast cancer at the age of 48. She had one child, Leo, with Kazan. Loden had another child, Marco, by her first husband, film and television Producer and film distributor, Larry Joachim, whom she had married in the 1950s.

Loden made her New York theater debut in 1957 in Compulsion and also appeared on stage in The Highest Tree with Robert Redford as well as Night Circus with Ben Gazzara. She joined the cast of The Ernie Kovacs Show as a "scantily clad" sidekick to Kovacs, a job that her first husband, television Producer and film distributor Larry Joachim, helped her attain. She said she owed a lot to Kovacs, as another Producer on the show had initially vetoed Kovacs' decision to hire her. In interviews, Loden said "Ernie felt sorry for me" and gave her another job as a stunt sidekick, rolling around in a rug or getting hit in the face with a pie.

In 1960, Loden appeared in Elia Kazan's film Wild River as Montgomery Clift’s secretary. She was perhaps better known for her role in Splendor in the Grass (1961), in which she played Warren Beatty's sister.

She famously portrayed "Maggie", a fictionalized version of Marilyn Monroe in Kazan's Lincoln Center Repertory Company stage production of After the Fall (1964), which was written by Monroe's former husband, Playwright Arthur Miller. Loden received a Tony award for best Actress for her performance in After the Fall, as well as an annual award of the Outer Circle, an organization of Writers who covered Broadway for national magazines. After the Fall reviews touted that Loden was the "new Jean Harlow" and a "blonde bombshell". She married Director Kazan, her second husband, in 1966.

While on safari with Kazan in 1966, a mutual friend, Harry Schuster, offered Loden $100,000 to make her own movie. Encouraged, she wrote the screenplay for Wanda. The story, an existential rumination on a poverty-stricken woman adrift in Pennsylvania coal country, did not attract any potential Directors to the project, including Kazan. So Loden directed it herself, made in collaboration with Cinematographer and Editor Nicholas T. Proferes, on a meager budget of $115,000.

Wanda is a semi-autobiographical portrait of a "passive, disconnected coal miner's wife who attaches herself to a petty crook." Innovative in its cinéma vérité and improvisational style, it was one of the few American films directed by a woman to be theatrically released at that time. Film critic David Thomson wrote, "Wanda is full of unexpected moments and raw atmosphere, never settling for cliché in situation or character." The film was the only American film accepted to, and which won, the International Critics' Prize at the Venice Film Festival in 1970, and was presented at the 1971 Cannes Film Festival. In 2010, with support from Gucci, the film was restored by the UCLA Film & Television Archive and screened at the Museum of Modern Art in Manhattan.

Loden was described as a shy, humble, statuesque and soft-spoken loner who was born in a small town in North Carolina (Marion). She was raised by her religious maternal grandparents, after her own parents had divorced, and her mother went to another town to find work. Loden moved to New York at the age of 16 and worked her way up as a pin-up girl, model, and Dancer at the famed Copacabana nightclub, before studying at the famed Actor’s Studio and becoming an actor.