Doom takes place in a research facility on Mars owned by the Union Aerospace Corporation, run by Dr. Samuel Hayden, a UAC scientist whose mind now inhabits an android body after having lost his original to brain cancer. Researchers at the UAC facility have attempted to draw energy from Hell, an alternative dimension inhabited by demons, in order to solve an energy crisis on Earth using the Argent Tower, which siphons energy and allows travel to and from Hell. To supplement their work, Hayden organizes several expeditions into Hell, bringing back captive demons and artifacts for study. Among them is a sarcophagus containing the Doom Slayer (along with his Praetor Suit), who the demons imprisoned after his earlier rampage through Hell.
The facility is overrun by demons after one of Hayden's researchers, Olivia Pierce, makes a pact with them and uses the Tower to open a portal to Hell. In desperation, Hayden releases the Doom Slayer from his sarcophagus to repel the demonic invasion and close the portal. The Doom Slayer recovers his Praetor Suit and fights his way through the overrun facility, where he realigns a comms satellite dish to get a lay of the land, all guided by the AI VEGA. After clearing out the facility core and preventing a meltdown, he pursues Pierce as he destroys the energy induction filters to Hayden's objections. He pursues Pierce up the tower, where she uses an Argent accumulator to open an explosive rift into Hell, destroying the Tower, and where the Slayer is sent back. Fighting his way to a teleporter, he returns to Mars and makes his way to a tram leading to Hayden. Hayden informs the Slayer of the Helix Stone, an artifact used to study and harness Hell's energy. Entering the Lazarus labs, he observes the Helix Stone, and he learns of the Well, where the portal is powered, and of the magical key-like blade, the Crucible. He makes another excursion into Hell after battling and defeating a contained Cyberdemon and activating its accumulator, and fights through a labyrinthine gauntlet to recover the Crucible from a trio of Hell Guards. Arriving at VEGA's facility in the frozen north, he destroys the AI (while also making a backup copy), using its power to enter the Well, which he uses the Crucible to destroy the portal's power source. Finally, he confronts Pierce, who is transformed by the demons into the monstrous Spider Mastermind, and kills her.
Upon the Doom Slayer's return to Mars, Hayden confiscates the Crucible, which he plans to use in his research. Despite all that has happened, he insists that Earth is too desperate for energy to give up. To keep the Doom Slayer from interfering with his plans, Hayden teleports him to an undisclosed location, saying that they will meet again.