Ridley Scott's science fiction blockbuster focused on a team of space travellers - including Charlize Theron, Michael Fassbender and Noomi Rapace - who discover a map on Earth that may lead them to discover the origins of mankind.
The paper hit out at Scott's loose Alien prequel for "[mishandling] the delicate questions raised by... the battle eternal between good and evil in yet another attempt to steal the secret of immortality".
L'Osservatore Romano has previously attacked The Da Vinci Code, and was particularly critical of the storyline for James Cameron's Avatar.
Prometheus grossed more than $398 million at the worldwide box office and is due for release on Blu-ray and DVD on October 8.
A sequel, which will see Fassbender and Rapace's characters return, with the rumoured title Paradise is said to be in the works.
Prometheus in pictures: