"Frida" begins with the traumatic accident Frida Kahlo suffered at the age of 18 when a car trolley collided with a bus she was riding. She is impaled by a metal pole and the injuries she sustained plague her for the rest of her life. To help her through convalescence, her father brings her a canvas upon which to start painting. Throughout the film a scene starts as a painting, then slowly dissolves into a live-action scene with actors.

Frida also details the artist's dysfunctional relationship with the muralist Diego Rivera. When Rivera proposes to Kahlo, she tells him she expects from him loyalty if not fidelity. Diego's appraisal of her painting ability is one of the reasons that she continues to paint. Throughout the marriage, Rivera cheats on her with a wide array of women, while the bisexual Kahlo takes on male and female lovers.

The two travel to New York City so that he may paint the mural Man at the Crossroads at the Rockefeller Center. While in the United States, Kahlo suffers a miscarriage and her mother dies in Mexico. Rivera refuses to compromise his communist vision of the work to the needs of the patron, Nelson Rockefeller; as a result, the mural is destroyed. The pair return to Mexico, with Rivera the more reluctant of the two.

Kahlo's sister Cristina moves in with the two at their San Ángel studio home to work as Rivera's assistant. Soon afterward, Kahlo discovers that Rivera is having an affair with her sister. She leaves him, and subsequently sinks into alcoholism. The couple reunite when he asks her to welcome and house Leon Trotsky, who has been granted political asylum in Mexico. She and Trotsky begin an affair which forces the married Trotsky to leave the safety of her Coyoacan home.

Kahlo leaves for Paris after Diego realizes she was unfaithful to him with Trotsky. When she returns to Mexico, he asks for a divorce. Soon afterwards, Trotsky is murdered in Mexico City. Rivera is temporarily a suspect and Kahlo is incarcerated in his place when he is not found. Rivera helps get her released.

Kahlo has her toes removed when they become gangrenous. Rivera asks her to remarry him and she agrees. Her health worsens, including the amputation of a leg, and she ultimately dies after finally having a solo exhibition of her paintings in Mexico.