Born in Rome, of Ukrainian ancestry, Nancy Brilli was introduced in cinema by Pasquale Squitieri, making her debut in a role of note in Claretta (1984). In 1990 she won a David di Donatello for Best Supporting Actress and a Silver Ribbon in the same category for the role of Sophie in Little Misunderstandings.
Nancy Brilli was married for two years to actor Massimo Ghini and later, again for two years, to director Luca Manfredi, son of actor and director Nino Manfredi. Previously she had a relationship with the songwriter Ivano Fossati.
In 1994 she underwent the removal of an ovarian cancer.
She is a niece of the racing driver Gastone Brilli-Peri.