In 1998, Mezzogiorno starred in the film Del perduto amore directed by Michele Placido, with Fabrizio Bentivoglio and Sergio Rubini (she was awarded the Nastro d'Argento, the Ciak d'Oro and Premio Pasinetti as best actress in a starring role) and, for the Italian National Television Network RaiDue, in a film made-for-TV Più leggero non basta ("A lighter burden to bear") in the role of a young girl with muscular dystrophy, directed by Elisabetta Lodoli with Stefano Accorsi.

In Italy, she worked with Puglielli in Tutta la conoscenza del mondo ("All There Is to Know"), and then, L'ultimo bacio ("The Last Kiss") directed by Gabriele Muccino with Stefano Accorsi and Stefania Sandrelli (winning the Premio Flaiano).

In 2001, Mezzogiorno appeared in the film Malefemmene with Ángela Molina and directed by Fabio Conversi, in the role of Francesca, who was imprisoned following a judicial error and came into contact with the reality of friendship and attachment which she had never imagined possible.

In 2002, she worked on the set of Ilaria Alpi - Il più crudele dei giorni, in the role of the protagonist, directed by Ferdinando Vicentini Orgnani (the film tells the tragic and dark story of the Italian TV journalist killed in Mogadiscio).

She also starred in France in the Holocaust-period TV drama Entrusted, directed by Giacomo Battiato, with Klaus Maria Brandauer, Thomas Brodie-Sangster and Steven Moyer, based on Loup Duran's best-seller.

In Italy, she starred in the film La finestra di fronte ("Facing windows") directed by Ferzan Özpetek, costarring Massimo Girotti and Raoul Bova.

She travelled to Colombia to become Fermina Daza, the principal female character from Love in the Time of Cholera based on the book written by Nobel Prize winner Gabriel García Márquez and directed by Mike Newell (Four Weddings and a Funeral).

After appearing in two films shot in 2008, Sono Viva and Palermo Shooting by Wim Wenders, in 2009 she achieved great international success with Vincere by Marco Bellocchio, selected for the official competition in Cannes and a solid candidate for the final award.