Bellucci's film career began in the early 1990s. In 1992 she made her first appearance in a major English-language film as one of Dracula's brides in Bram Stoker's Dracula. She became known and popular with worldwide audiences following her roles in Malèna, Brotherhood of the Wolf and Irréversible, though is perhaps best known for her role as Persephone in The Matrix Reloaded and The Matrix Revolutions followed by her portrayal of Mary Magdelene in The Passion of the Christ.

In a documentary about the film, The Big Question, she stated: "I am an agnostic, even though I respect and am interested in all religions. If there's something I believe in, it's a mysterious energy; the one that fills the oceans during tides, the one that unites nature and beings."

In 2003, Bellucci starred in Tears of the Sun as a doctor in Nigeria being rescued by the U.S., and in 2005 in the fantasy film The Brothers Grimm as a beautiful evil queen. Her latest films are The Stone Council, directed by the Frenchman Guillaume Nicloux (2006) and Manuale d'amore 2 (2007) where she portrays a physiotherapist who is the object of the desire of her patient. She was supposed to be seen portraying Indian politician Sonia Gandhi in the biopic Sonia, originally planned for release in 2007 but now shelved. September 2007 saw the release of Shoot 'Em Up, where she plays a prostitute opposite Clive Owen. She dubbed her own voice for the French and Italian releases of the film. She filmed Le Deuxième souffle with Daniel Auteuil, Michel Blanc and Eric Cantona (2006). Bellucci also voiced Kaileena in the video game Prince of Persia: Warrior Within, and the French voice of Cappy for the French version of the 2005 animated movie Robots. In 2007, she appeared in Heartango, a movie for Intimissimi, with José Fidalgo and directed by Gabriele Muccino.

• 1:30 Train (2010) (announced)
• Empires of the Deep (2010) (pre-production) (rumored) .... Mermaid Queen
• Baaria - La porta del vento (2009) (post-production)
• Ne te retourne pas (2009) (completed)
  
• The Private Lives of Pippa Lee (2009) .... Gigi Lee
• Uomo che ama, L' (2008) .... Alba
  ... aka The Man Who Loves (International: English title)
• Sanguepazzo (2008) .... Luisa Ferida
  ... aka Une histoire italienne (France)
  ... aka Wild Blood (International: English title: festival title)
• Deuxième souffle, Le (2007) .... Simona - dite 'Manouche'
  ... aka The Second Wind (International: English title)
• Shoot 'Em Up (2007) .... Donna Quintano
• Manuale d'amore 2 (Capitoli successivi) (2007) .... Lucia
  ... aka Manual of Love 2 (Australia: TV title)
• Heartango (2007) .... L'inafferrabile/La passionale/L'indecisa/La curiosa/L'aggressiva/La mamma/La premurosa
• Concile de pierre, Le (2006) .... Laura Siprien
  ... aka Concilio di pietra, Il (Italy: literal title)
  ... aka Eletto, L' (Italy)
  ... aka Liu San - Wächter des Lebens (Germany: DVD title)
  ... aka The Stone Council (International: English title)
• N (Io e Napoleone) (2006) .... Baronessa Emilia Speziali
  ... aka N (Io e Napoleone) (International: English title)
  ... aka N - Napoléon (France)
  ... aka N.: Napoleon & Me (International: English title)
  ... aka Napoleon & moi (France)
  ... aka Napoleon (et moi) (France)
  ... aka Napoleon and Me (USA: festival title)
• Sheitan (2006) .... La belle vampiresse
  ... aka Satan (International: English title: literal title) (UK: DVD title)
• Combien tu m'aimes? (2005) .... Daniela
  ... aka How Much Do You Love Me? (Australia) (International: English title)
  ... aka Per sesso o per amore? (Italy)
• The Brothers Grimm (2005) .... Mirror Queen