The game begins with the player character's death and transformation into a vampire in late October 2004. The plot revolves around a mysterious archaeological artifact called the Ankaran Sarcophagus, believed to contain the body of an ancient vampire (Antediluvian) in torpor. As the various factions of Los Angeles conspire to obtain this artifact, or to foil each other's attempts to do so, the player must decide whom to trust: Prince Sebastian LaCroix, Regent Maximillian Strauss, the Anarchs, the Kuei-Jin, or only him/herself. However, the in-game storyline does not change regardless of what is done, and all the core missions still need to be completed. For example, if the player decides to side with the Anarchs, they will still need to obey Prince LaCroix, as they are told to act like they are still loyal. The only storyline-affecting choice is when the character chooses his or her allegiance near the end of the game, though prior choices can affect which of these allegiances are available.
The game begins with the creation of a male or female vampire character of one of seven Camarilla clans. Players can choose to manually pick the clan their character will join and their character's statistics, or they can answer a series of questions to be assigned stats. Once a character has been created, the introductory sequence begins with an in-game cinematic of a lascivious vampire Sire 'embracing' the player's character; draining the character of blood, and beginning the player's transformation into a vampire. Shortly after the Embrace, both the player and their Sire are captured by the Los Angeles Camarilla for what is revealed to have been an unauthorized act, violating the organization's strict rules on vampire creation. The player's Sire is executed at the order of the Prince, Sebastian LaCroix, who is the leader of the Camarilla in Los Angeles. The player is spared a similar fate when Nines Rodriguez, a Brujah who was in the audience as a representative of the Anarch community, jumps up and calls out the Prince, who then relents.
A sarcophagus that was previously discovered about a thousand years ago by Church authorities and subsequently re-buried, it was rediscovered by the Norwegian archaeologist Dr. Johansen, and was on its way to an American museum for examination. Bloody handprints on its surface found while on board the Elizabeth Dane indicate it may have been opened from the inside. The Vampires of Los Angeles circulate rumors that the sarcophagus held an Antediluvian, a third-generation vampire, one of the eldest and most powerful in existence, and also a sign of Gehenna, the Vampire "end of days" scenario. The vast majority of them believe that it should never be opened, or destroyed entirely. Beckett believes it to hold nothing more sinister than the mummy of an Assyrian king, a hypothesis confirmed by Dr. Johansen, who however brings to note that this king was attributed with 250 years worth of achievements. While he notes that previous royal names were probably just erased, or that the name was passed onto subsequent generations, he chuckles at the idea that the king could have lived to 250 years of age. The surface murals depict figures drinking bowls of blood, which Dr. Johansen stipulates was more of a result of rituals or simply the royalty's way of dealing with porphyric disorders, rather than any proof that whatever lies inside is a vampire.