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The film deals with complex issues such as AIDS, transvestitism, sexual identity, gender, religion, faith, and existentialism; the characters are presented in a straightforward and mostly unromanticized and non-judgemental fashion but with an edge of dark humour. The film won an Academy Award for Best Foreign Language Film in 2000.

The title is a play on the film title All About Eve, of which Esteban is a fan. Watching the film with his mother, he complains that the translation of the title into Spanish is a poor one, and should have been "Todo sobre Eva." "Todo sobre mi madre" is also the title of an essay he is writing at the time of his death.

One night after watching a play of Tennessee Williams' A Streetcar Named Desire Esteban is running after the car of the actress who played Blanche DuBois to get an autograph when he is hit by a car and dies. Manuela sees the accident and, despondent, leaves Madrid to visit her son's father, Lola, who is a transvestite and a prostitute in Barcelona, and inform him of the existence of the son he never knew. While in Barcelona, Manuela reunites with an old friend, a warm and witty transsexual prostitute named Agrado. She also meets and becomes deeply involved with Sister Rosa (played by Penélope Cruz), a young, pregnant nun who has known Manuela's ex-husband; and the actress that her son had admired.

The film was widely regarded as Almodóvar's finest and most mature to date, and was named by Richard Schickel of Time Magazine, among other critics, as the best of the year.