Two years after the events of 2016's Doom, Earth has been overrun by demonic forces, wiping out 60% of the planet's population, under the now-corrupted Union Aerospace Corporation. What remains of humanity has either fled Earth or have banded together as part of ARC, a resistance movement initially formed to stop the invasion but have gone into hiding after suffering heavy losses. The Doom Slayer, having previously been betrayed and teleported away by Dr. Samuel Hayden, returns to Earth with a new arsenal of weapons and a satellite fortress controlled by the AI VEGA to quell the demonic invasion by killing the Hell Priests; Deag’s Nilox, Ranak, and Grav. The priests serve an angelic being known as the Khan Maykr who seeks to sacrifice mankind. The Slayer teleports to Los Angeles and kills Deag Nilox, but the Khan Maykr teleports the two remaining priests to unknown locations, forcing the Slayer to continue searching.

After retrieving a celestial locator from the Sentinel world of Exultia, the Slayer travels to Hell to retrieve a power source from a fallen Sentinel known as the Betrayer. He warns the Slayer that humanity's time has come before giving him the power source. VEGA directs the Slayer to a citadel in the Arctic where Deag Ranak has taken refuge; the Slayer retrieves his Super Shotgun and defeats the Priest's Doom Hunter guardians before killing him.

In response to Deag Ranak’s death, the Khan Maykr moves Deag Grav to a secure location and accelerates the invasion of Earth. Forced to change tactics, the Slayer destroys the Super Gore Nest in central Europe, where the invasion began. After destroying the nest, Vega suggests finding Dr. Hayden, who knows the location of Deag Grav. The Slayer makes his way to a compound where he retrieves Hayden’s robot chassis as well as the Crucible before facing a Marauder, a demonic sentinel sent to stop the Slayer.

Upon uploading Hayden’s mind into the fortress, he reveals Deag Grav is hiding on Sentinel Prime. With the only portal to Sentinel Prime located in the ancient city of Hebeth in Mars’s core, the Slayer travels to a facility on Phobos where he uses the BFG 10000 to shoot a hole in Mars and makes his way to Hebeth. After reaching Sentinel Prime, the Slayer discovers Deag Grav hiding in a gladiatorial arena. After killing Deag Grav’s guardian, the Gladiator, the final Hell Priest warns the Slayer that he will be ostracized from the Sentinels if he kills him on Sentinel ground. Unfazed, the Slayer kills Deag Grav and teleports back to his fortress.

Despite stopping the demons' invasion of Earth, the Slayer's fortress is shut down remotely by the Khan Maykr, who resolves to resurrect the demon world-eating super-predator, the Icon of Sin to consume the mankind. However, the Slayer uses the demonic Crucible's latent Argent energy to reactivate the ship and travels to Argent d'Nur to retrieve his own Crucible from his time in the Sentinels. It is revealed that the Khan Makyr formed an alliance with Hell to produce Argent energy, which is created through the mass sacrifice and torture of human souls. In return for providing worlds for Hell to invade, the Maykrs receive a share of the Argent energy produced by Hell which allows their own dimension, Urdak, to survive.

With the Icon of Sin on Urdak, Hayden directs the Slayer through Hell's massive citadel, Nekravol, until he finds a portal leading to the Maykr’s dimension. He then finds the Khan Maykr and stops the ceremony by using the Betrayer's dagger to destroy the Icon of Sin’s heart. Free from Maykr control, the Icon of Sin awakens from its dormant state and manages to teleport to Earth. The Icon of Sin’s awakening also breaks the alliance between the Maykrs and Demons, who proceed to invade Urdak. The Khan Maykr confronts the Slayer over his actions, saying that Urdak must destroy Earth to survive. They battle and the Slayer manages to kill the Khan Maykr before taking a portal back to Earth to confront the Icon of Sin. After an intense battle, the Slayer kills the Icon of Sin by stabbing it in the head with the Crucible, putting an end to Hell’s invasion of Earth.


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