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 (whose son was corrupted into the Icon of Sin). He warns the Slayer that humanity's time has come before giving him the power source, and a special dagger to use on his son's heart. VEGA directs the Slayer to a citadel in the Arctic where Deag Ranak has taken refuge, and the Slayer kills him after defeating his guardian Doom Hunters.
In response, the Khan Maykr moves Deag Grav to a hidden 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. With no leads on finding the last Hell Priest, VEGA suggests finding Dr. Hayden, who knows the location of Deag Grav. The Slayer makes his way to an ARC compound where he retrieves Hayden's robotic shell, 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' core, to which there is no immediate access. The Slayer then travels to a facility on Phobos where he uses the BFG 10,000 orbital cannon to shoot a hole in Mars, which he uses to reach Hebeth. After reaching Sentinel Prime, flashbacks reveal the Slayer to be the same 'Doomguy' from the original games. Found badly wounded by Sentinels, Doomguy was brought before the Deags and was forced to fight in a gladiatorial arena. Impressed by Doomguy’s ruthlessness in battle, the Deags inducted him into the Sentinels, while the Khan Maykr inquires into Doomguy's knowledge of the Demons. In the present, the Slayer finds Deag Grav in the arena and defeats a massive demon known as the Gladiator. Despite knowing that it is against Sentinel law to murder Deag Grav on sacred ground, the Slayer kills him anyway and returns to the fortress.
Upon his return, the Slayer's fortress is shut down remotely by the Khan Maykr to prevent any further interference in her plans. She reveals her intentions to resurrect the Icon of Sin, the world-eating super-predator, to consume mankind before having the Slayer attacked by demons. Surviving the ambush, the Slayer uses the demonic Crucible's latent Argent energy to reactivate the fortress, and travels to Argent d'Nur to retrieve his own Crucible from his time in the Sentinels.
Further flashbacks reveal that during the ill-fated battle of Argent D'Nur, a rogue Maykr known as the Seraphim had imbued Doomguy with superhuman abilities, transforming him into the Doom Slayer. After retrieving the hilt of the Crucible, it is revealed that the Khan Maykr formed an alliance with Hell to produce Argent energy, which is created through the mass sacrifice 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.
Hayden directs the Slayer through Hell's massive citadel, Nekravol, until he finds a portal leading to the Urdak. He then finds the Khan Maykr and halts the awakening ceremony by using the Betrayer's dagger to destroy the Icon's heart. Free from Maykr control, the Icon of Sin awakens from its dormant state and teleports to Earth. With the dimensional barrier destroyed, the Demons break their pact with the Maykrs and proceed to invade Urdak. The Khan Maykr confronts the Slayer, saying that Urdak must destroy Earth to survive. They battle and the Slayer kills the Khan Maykr before taking a portal back to Earth to confront the Icon of Sin, although VEGA is left behind to ensure the portal stays open. After an intense battle across the cityscape, 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. As the Slayer walks away, King Novik, leader of the Night Sentinels, states via voiceover how the Slayer's fight is "eternal".
After returning to the ARC Carrier, the Seraphim tasks the Slayer to find and retrieve the Father's life sphere from the Blood Swamps of Hell in order to return the Father to physical form. After fighting his way through the Blood Swamps, the Slayer finds and retrieves the Father's life sphere. However, the Slayer chooses to destroy the sphere rather than hand it to the Seraphim and instead retrieves the Dark Lord's life sphere before returning to the ARC Carrier.
Despite most of the Carrier's crew evacuating upon seeing the Dark Lord's life sphere, a lone intern stays to help the Slayer reach Urdak assuming that the Slayer intends to resurrect and destroy the Dark Lord, which in effect will destroy all demons. Upon reaching the corrupted Urdak, the Doom Slayer fights his way to the Luminarium where anyone who has a life sphere may activate it. However, the Slayer is confronted by the Seraphim upon reaching the Luminarium's entrance. Consumed by Urdak's demonic corruption, the Seraphim is transformed into a demon and after a lengthy battle is ultimately defeated by the Slayer and is teleported away by the Father. Despite being warned that bringing the Dark Lord into physical form is irreversible, the Doom Slayer proceeds to summon him, and the Primeval manifests as a copy of the Slayer himself.
During his journey he is met by the Betrayer, who gives the Slayer his Sentinel Hammer for putting his son to rest. After acquiring the crystal, the Slayer heads back to Earth which has been invaded by demons again due to the death of the Khan Maykr and the demonic invasion of Urdak. Fighting his way through the demons, the Slayer arrives at the Gate of Divum and activates it. He is then teleported to the city of Immora, where the Dark Lord awaits. Valen and the rest of the Night Sentinels also arrive to aid the Slayer, to his surprise. The Slayer rips and tears his way through the demons in his way while the Sentinels fight outside and eventually arrives at another portal. Going through it, he is greeted by the Dark Lord, where they proceed to fight. After sustaining damage, the Dark Lord reveals to the Slayer that the Maykrs lied to him and that he is the real Father, with VEGA confirming this to be true. Moments after, the Dark Lord is ultimately defeated. With his dying breath, the Dark Lord asks if the Slayer has anything to say him before he is struck down, to which the Slayer responds with, "No." After stabbing Davoth in the chest, all demons outside of Hell disappear. However, the Slayer starts to become dizzy and eventually falls unconscious. He is then seen being sealed in his sarcophagus by three Maykrs.
