Pietrangeli was born in Rome. He started in the film industry by writing movie reviews for Italian cinema magazines such as Bianco e Nero and Cinema.
As a screenwriter, his works include Ossessione and La terra trema directed by Luchino Visconti, Fabiola directed by Alessandro Blasetti, and Europa '51 directed by Roberto Rossellini.
Pietrangeli's own directing debut was Il sole negli occhi, a 1953 film starring Gabriele Ferzetti. This was followed by the Alberto Sordi comedies Lo scapolo (1956) and Souvenir d'Italie (1957).
The director's career highlights include Adua e le compagne (1960), a drama with Marcello Mastroianni and Simone Signoret, the supernatural comedy Fantasmi a Roma (1961), again with Mastroianni, Il magnifico cornuto (1964), a comedy of adultery starring Claudia Cardinale and Ugo Tognazzi, and the comedy-drama Io la conoscevo bene (1965) with Stefania Sandrelli.
He won the Nastro d'Argento for Best Director for Io la conoscevo bene.
Pietrangeli died from drowning by accident in the Gulf of Gaeta in 1968, while working on the film Come, quando, perché. The movie was completed by his friend, director Valerio Zurlini.