In 2147, two years after the events of Doom 3, the UAC detects a strange signal from one of its Martian satellites, and consequently sends a team in to investigate. After this team finds the Hellstone in the process, the forces of Hell attempt to retake the object from the player, a marine combat engineer who is working for Dr. Elizabeth McNeil. McNeil, an unseen character in Doom 3, was the whistleblower who notified counselor Elliot Swann and Jack Campbell of Malcolm Betrugers mysterious activities at the beginning of Doom 3.

After fighting his way through the complex, the marine eventually meets up with McNeil in the Phobos Labs. She tells him that the only way to destroy the Hellstone is to return it to where it came from: Hell. The marine powers down the base to re-route power to one of the teleporters to reach the Delta Labs, where the main teleporter to Hell is located. This is already after he has defeated the three Hunters, the demons in charge of guarding and now retrieving the Hellstone.

The marine arrives in Hell and battles his way to Betruger, who has become the Maledict. After some fighting, Betruger bites the marine, but before he can eat him, the marine shoves the Hellstone down Betrugers throat, causing him to dematerialize. Only his skull remains. The game ends with a bright white light, followed by McNeils voice saying, Marine?... Welcome home.