Doctor Jonathan Reid, returning to London from the Great War in 1918, awakes in a mass grave as a vampire. Overwhelmed with bloodlust, he inadvertently kills his sister Mary, who was searching for his body nearby. Jonathan takes shelter from vampire hunters in an abandoned house and starts hearing the disembodied voice of his maker, a typical feature in the progeny of vampires. Realising London is profuse with corpses, he follows a blood trail to a bar. The bartender points Jonathan to William Bishop, a suspicious patron. Bishop is caught feeding on a man named Sean Hampton and is killed by the vampire Lady Ashbury. Doctor Edgar Swansea rescues Hampton and hires Jonathan to practice medicine at Pembroke Hospital.
The player controls Jonathan E. Reid, a doctor who was made into a vampire, and whose thirst for blood compels him to kill innocent people. To do this successfully, he must study and change his targets' habits, collect clues, and maintain relationships with the sixty citizens under his care in London, which serves as a fictionalised semi-open world built around hubs of neighbourhoods tethered to other areas. A skill tree facilitates the improvement of abilities, which is fuelled by experience points gained from blood and, alternatively, investigation. Feeding on human blood provides nourishment in addition to unlocking new vampiric powers. Abilities can be manually activated and passively upgraded. Active skills afford defensive, aggressive, healing, and tactical measures; passive skills increase health, stamina, the blood gauge and absorption, bite damage and regeneration, and carry capacity.