The game is set in March 1937, approximately 98 years after the events of The Dark Descent. The story follows Anastasie “Tasi” Trianon, a French archeologist on an expedition in colonial Africa.
After her plane crash-lands in a desert in Algeria, she wakes up to discover that all of her companions have gone missing and she has no recollection of what happened immediately after the crash.
Determined to find her husband Salim, Tasi braves the dangers of the desert to follow the trail of her expedition. As she navigates a cave, Tasi realizes she has somehow come into possession of a Traveler's Amulet, an alien device that allows her to travel through Rifts to a dead alien world.
She also discovers that she is pregnant. Tasi eventually finds Salim's corpse; he had already succumbed to mortal wounds he suffered in the plane crash. Distraught, Tasi continues on to try and find the rest of the expedition.
Upon exiting the cave, Tasi comes across an abandoned French fort and quickly discovers the entire garrison had been slaughtered by some unknown force. She manages to get into contact with an expedition survivor, Dr. Metzier, who instructs her to head to a nearby village he had managed to find.
Tasi travels deep under the fort to find an exit, and soon encounters grotesque and mutated ghouls that stalk the tunnels. She is able to make her way out of the fort, but is caught in a cave-in and falls into ancient ruins that once belonged to a highly advanced but now extinct society.
As she studies the ruins, Tasi learns that the facility was built by an alien race dubbed the Gate Builders, who had the ability to traverse worlds and extend their lives thanks to the power of vitae, a substance which they obtained by torturing humans on a mass scale.
However, an experiment caused the Gate on their homeworld to malfunction and destroy itself, wiping out the Gate Builders and spreading the Shadow, a dangerous force that manifests in red tumor-like growths. Tasi also comes across signs of a previous expedition led by Professor Thurston Herbert, where Daniel broke the Orb and incurred the Shadow's wrath.
She also discovers to her horror that one of her expedition members, Leon, was turned into a ghoul. She also rescues another expedition member, Richard, but ends up killing him in a rage when he betrays her and attempts to leave her to die.
Tasi is able to activate a teleporter to transport herself to the village, though she begins to go into labor due to the stress of her journey. She then encounters another expedition member, Yasmin, who is in the process of turning into a ghoul.
She admits that she lost control of herself and slaughtered all of the villagers, and warns Tasi to run away from her. Dr. Metzier then arrives and shoots Yasmin dead before she can attack Tasi.
He helps Tasi deliver her daughter, whom she names Amari, but then takes her away, claiming Amari is needed to reverse the ghoul curse placed on them. Tasi chases after Dr. Metzier, who uses the Traveler's Amulet to travel to the Gate Builder world.
During the pursuit, Tasi begins to recover her full memories. Shortly after the plane crash, the Empress of the Gate Builders approached Tasi and the expedition.
The Empress, longing to be a mother after vitae treatment for an unknown affliction rendered her infertile, gave them the Traveler's Amulet and promised to save them if Tasi handed over Amari. Still traumatized by the loss of her previous daughter Alys, Tasi refused the deal.
Before sending them back to Earth, the Empress tricked the expedition into drinking from a special fountain that inflicted the ghoul curse on them, which would make it easier for her to control them.
Tasi is able to catch up to Dr. Metzier and kill him. The Empress then warns Tasi that Amari is afflicted with the same illness that killed Alys, and is doomed to suffer the same fate.
She pleads with Tasi to allow Amari to stay with her, as she can provide an endless supply of vitae to Amari to suppress her illness and allow her to live a full life. Tasi is left with the choice of leaving Amari behind, fighting the Empress, or fleeing with Amari.
If Tasi leaves Amari behind, the Empress commends her for making the right choice and fully turns Tasi into a ghoul. As a ghoul, Tasi roams the ruins of the Gate Builder world with only fragmented memories of Amari.
If Tasi decides to fight the Empress, she injects Red Flesh into the Empress' vitae supply, killing the Empress and destroying what little is left of the Gate Builder civilization. While this euthanises the humans being tortured for their Vitae, both Tasi and Amari are swallowed by the Shadow's growths and perish as well.
If Tasi decides to flee with Amari, she is able to activate a teleporter that sends her and Amari to Paris and beyond the Empress's reach. Tasi and Amari emerge in Paris, with both of them facing an uncertain future.