Born and raised in Rome in an intellectual family (her elder brother is the political and economic theorist Daniele Archibugi), she started to study acting with Alessandro Fersen and graduated in Film Direction from the Centro Sperimentale di Cinematografia in Rome.
From 1980 to 1983 she directed short films such as La piccola avventura (1981), about handicapped children, and acted in La caduta degli angeli ribelli (1981), directed by Marco Tullio Giordana and starring Alida Valli. She filmed the short Un sogno truffato in 1984 with the Lualdi-Interlenghi duo and played the neurotic intellectual woman in Giuseppe Bertolucci's film Segreti, segreti (1986), again starring Alida Valli, and with Rossana Podestà, Lea Massari, Lina Sastri and Stefania Sandrelli.
She wrote the script of L'estate sta finendo in 1987.
Her long film debut came with Mignon è partita in 1988, a bitter family portrait that examines the first experiences and disappointments of teenage love. The film won 5 David di Donatello awards: Best New Director, Best Actress (Stefania Sandrelli), Best Supporting Actor ( Massimo Dapporto), Best Script and Best Sound. During the filming, she fell in love with the composer Battista Lena, who wrote the score for her film.
Her second film, Verso sera (1990), starring Marcello Mastroianni and Sandrine Bonnaire, was a success. It was named Best Film of the year at David di Donatello Awards. The film was entered into the 17th Moscow International Film Festival.
Her third film, The Great Pumpkin (Il grande cocomero) (1993), starring Sergio Castellitto and Anna Galiena, won 2 David di Donatello awards, for Best Film and Best Script, and was another success. It was also screened in the Un Certain Regard section at the 1993 Cannes Film Festival.
In 1994 she filmed Con gli occhi chiusi, based on Federico Tozzi's novel, starring Laura Betti, Stefania Sandrelli, Sergio Castellitto and Debora Caprioglio. Her next films were La strana storia della banda sonora (1997) and L'albero delle pere (1998).
Ornella Muti starred in Domani in (2001), a film about the 1997 Umbria and Marche earthquake. She collaborated on Pasolini-le ragioni di un sogno (2001), and she filmed Giovanna Mezzogiorno and Roberto Citran in Lezioni di volo (2005).Mignon è partita (1988)
Verso sera (1990)
The Great Pumpkin (1993)
Con gli occhi chiusi (1994)
La strana storia della banda sonora (1997)
L'albero delle pere (1998)
Renzo e Lucia (2004)
Lezioni di volo (2006)
Questione di cuore (2009)
Like Crazy (2016)