DOOM 64 picks up where all the other DOOM games left off. After tearing through space, hell, and wherever else in the previous games, the Space Marine thought that the threat of the demons was finally past. Of course, one survived, and it is currently reanimating all of the fallen monsters in a last-ditch attempt to revitalize their evil mission. The player's task is to finally rid the universe of all the crazy hellions, from the dead guy with the pistol to the rocket-spewing Cyberdemon.

The game is very different from the original DOOM; it has larger sprites, pseudo 3D, new textures, scrolling skies, custom scripting which allows for morphing environments, spawning items and new character animations. The levels are completely new and the game features the Unmaker weapon and an alternative end boss.