Angels & Demons brings an ancient secret organization, the Illuminati, and the Vatican together in a present-day battle for control. Harvard symbologist Robert Langdon must join forces with scientist Vittoria Vetra in a frantic race to save the Vatican from a powerful bomb which threatens to destroy it and the cardinals who have gathered within the Sistine Chapel to elect the next Pope. Their journey takes them across Rome and into cathedrals, secret archives and the Illuminati lair. Along the way, they uncover many secrets, including who is responsible for the threat to the Vatican. In the end, they save the Vatican and the cardinals from harm.

Langdon is summoned to Switzerland when it is discovered that an Illuminati brand was used to mark a dead man's chest. He meets Vittoria, the dead man's daughter, and Maximillian Kohler, the director of CERN, the Conseil Europyen pour la Recherche Nuclyaire, or European Council for Nuclear Research. Vittoria and her father have created a sample of antimatter, a highly unstable material, which has been stolen. They receive a call from the Vatican, stating that they have an unknown canister with CERN's logo on it. Langdon and Vittoria race to Rome, only to find that the canister endangers not only the physical structures there but also the College of Cardinals, who have gathered to elect a new Pope. Four cardinals are also missing.

The camerlengo, who is in charge of the Vatican until a new Pope is elected, receives a call from someone who claims that the Illuminati are behind all of the actions that night. He says that he will kill one of the missing cardinals each hour. Langdon and Vittoria think that if they can capture the killer, they can find the location of the antimatter. They find an ancient booklet which points to four sites called the Altars of Science. These sites form a pathway to the Church of Illumination, the Illuminati lair.

At each site, Langdon and Vittoria find one of the dead cardinals, branded with another Illuminati brand. The cardinals are killed in ways that correspond to the four brands: earth, air, fire and water. Vittoria is captured by the killer at the third site. Langdon continues to follow the clues, fighting with the killer at the third and fourth sites. He finally locates the Church of Illumination, and he and Vittoria kill the Hassassin, or killer.

Kohler arrives at the Vatican, saying that he has information. Langdon believes that he is behind the plot. Kohler is killed in the camerlengo's office, but he gives Langdon a tape before dying. The camerlengo has been branded. He seems to have a vision from God and rushes from St. Peter's Square into the basilica, returning with the canister of antimatter. He and Langdon climb in a helicopter. As time runs out on the antimatter canister, the camerlengo jumps from the helicopter. Langdon also jumps, although he does not have a parachute. The antimatter explodes high above Rome.

The camerlengo glides down to land on top of St. Peter's Basilica. People worldwide believe that a miracle has occurred. Langdon lands in the Tiber River and is taken to a hospital. There, he discovers the tape from Kohler. He takes the tape to the Sistine Chapel, where the College of Cardinals is set to elect the camerlengo Pope. The tape contains a recording of the camerlengo admitting that he planned everything in order to bring people back to the church. The camerlengo lights himself on fire. The Vatican asks Langdon and Vittoria to keep quiet about what really happened that night if they feel that this is right in their heart.