The film follows a man, Jack (Jesse Metcalfe), faking insanity in order to save his sister, Lily (Kiele Sanchez), who has been involuntarily institutionalized. The siblings soon find that the strange doctor at the asylum, Mr. Gianetti (Peter Stormare), has been testing an experimental compound, orphium, on the patients that seems to be turning them into flesh-eating zombies; Loomis (Kurt Caceres), another patient, spreads the infection. The two siblings band together with a terminally paranoid man, Dave (Kevin Sussman), and a helpful nurse, Nancy (Olivia Munn), in the hopes of finding a way out of the asylum. They are attacked by most of the prisoners and staff, who kill Nancy; while on the 4th floor, they encounter the doctor, who gives Dave an icepick lobotomy, incapacitating him; he attempts to get Jack too, but ends up being infected by Loomis. At the end of the film, as the two siblings are in a police car heading to the asylum to investigate, the officers (Mark Kelly & Sharon Schaffer) accidentally let the patients escape into the outside world. It ends with a panning shot, revealing the city below the asylum's hillside location. The secondary plot focuses on the affair between Charles (Evan Parke) and Heather (Lisa Athrowe).

The story tells the investigation started by symbolist Robert Langdon and a good-looking cryptologist, Sophie Neveu, around the murder of a Museum Louvre's curator. In fact, the unfortunate murdered man was Sophie's grandfather, and the corpse was found with a series of symbols and codes, like a pentagram and a Fibonacci number sequence. But police detective Fache will begin to chase Langdon, who escapes after receiving a warning about the captain's real intentions. Sophie has with her a kind of key with dots and number 24 engraved on it, which opens to her and Langdon a big complex investigation that involves a supposedly heretic theory: Jesus Christ and Mary Magdalene were, in fact, a couple who produced a daughter named Sara. A millenarian sect called The Priory of Sion has kept for centuries the secret of that matter. A masochist and kind of psychopath albino monk, Sibilas, an Opus Dei member, will chase Langdon and Sophie as well, in order to impede that they solve the mystery of Christ and Mary Magdalene, and also the real meaning and location of the Holy Grail. A passionate British researcher, will help Langdon in his quest, revealing to them several symbolisms in Da Vinci's master work The Last Supper, traveling to mythical places in the UK, such as The Church Temple, where it is believed that a group of Templars Knights are buried, and Sir Isaac Newton's tomb at Westminster Abbey, where are located some of the main keys to solve the Holy Grail's mystery.