The Angel of Darkness follows on from events in Tomb Raider: The Last Revelation and Tomb Raider: Chronicles, where Lara Croft was presumed dead. An unspecified time later, Lara arrives in Paris at the request of her former mentor, Werner Von Croy, who was tasked by a man named Eckhardt to find a set of artefacts known as the Obscura Paintings. The city, and Von Croy, are gripped with fear over a serial killer the press has dubbed the "Monstrum". During an argument between Lara and Von Croy, an unknown force attacks them, and Lara is knocked unconscious. She wakes to find Von Croy dead and her memories of the attack blurred. Suspected of his murder, Lara goes on the run. After retrieving Von Croy's journal from a colleague named Margot Carvier, she learns that Von Croy discovered the location of the fourth Obscura Painting beneath the Louvre; during her time in Paris getting help from local businessman and mob boss Louis Bouchard, Lara is stalked by Kurtis Trent, the last survivor of a society called the Lux Veritatis who are sworn to fight against Eckhardt's plans. After infiltrating the Louvre, she learns that the paintings hide pieces of the Sanglyph, an alchemical artefact created by Eckhardt hundreds of years before. The paintings were seized and hidden by the Lux Veritatis centuries before. After retrieving the Painting from its hiding place, Lara is ambushed by Kurtis and robbed of the Painting.
The two escape the Louvre as it is assaulted by mercenaries, with Kurtis using a magical disc to keep both Lara and the mercenaries at bay; both are knocked out by a shape-shifting stranger. Lara is rescued by Bouchard, who takes her to Von Croy's apartment to find further clues. At the apartment, Lara relives the murder and realizes that a strange man, revealed to be Eckhardt, had knocked her unconscious and killed Von Croy. However, Bouchard sends an assassin to kill Lara; she is able to eliminate the hitman and heads for Prague, where a new Monstrum killing has taken place. Arriving in Prague, she finds the location of the final Painting and re-encounters a captive Bouchard. He reveals that Eckhardt is planning to use the Sanglyph to awaken the Cubiculum Nephili, the last surviving member of the hostile Nephilim race, and breed them back into existence. Bouchard is later murdered by Eckhardt, who is revealed to have been killing and extracting samples for his experiments under the guise of the Monstrum. Lara infiltrates Eckhardt's headquarters in the Strahov Sanitarium, with help from an investigative journalist named Luddick. The journalist is later captured and murdered by Eckhardt. Lara encounters members of the Cabal, a secret society that shares Eckhardt's ambitions. While going through the complex, she switches off the power, releasing a rabid creature called the Proto-Nephilim. Later on, Lara is locked in a containment area by Kurtis so he can turn the power back on without interference.
Kurtis succeeds, finding his way through the Sanatorium and killing the Proto-Nephilim. Forming an alliance, Lara retrieves the final Painting, while Kurtis goes to retrieve a Periapt Shard, one of three magical daggers which can kill Eckhardt. After retrieving the Painting, Lara is forced by Eckhardt to hand over the Paintings to save Kurtis's life. After Eckhardt releases one of the Cabal's monsters on them, Kurtis helps Lara escape - giving her the two Periapt Shards in his possession - before killing the monster, being seriously wounded in the process. Lara recovers the final Shard and reaches Eckhardt, who reforms the Sanglyph and begins reviving the Cubiculum Nephili. Lara succeeds in wounding him but is stopped by Karel, Eckhardt's right-hand man. Karel proceeds to kill Eckhardt, revealing himself to be a Nephilim who has been secretly aiding Lara using his influence in the Cabal and shape-shifting abilities. He offers Lara the chance to join him, but Lara refuses after remembering that it was Karel who murdered Von Croy in Eckhardt's form. Lara uses the Sanglyph to destroy the Cubiculum Nephili, causing an explosion that kills Karel. On her way out, she finds Kurtis's weapon and it leads her toward the monster's chamber. Smiling, Lara walks through the door into the shadows, ending the game.