Space Siege takes place in the far future, where Earth has just been destroyed by the Kerak, an insect-like race of aliens that are seeking to exterminate humanity in retaliation for mankind's colonization of their homeworld, Elysium IV.

Players take the role of security officer Seth Walker who, along with his robot sidekick HR-V (pronounced "Harvey"), is tasked with repelling the Kerak attack on the ship.

Throughout the game, the player is given the option of replacing their body parts with cybernetic augmentations, which allow Seth to battle the Kerak more effectively, at the nebulous cost of "some of his humanity".

Gina is fiercely opposed to cybernetic augmentation, Jake supports it fervently, and Dr. DeSoto is in favour of it to a certain extent, believing that man should not replace all their body parts.

Later in the game, it is revealed that the AI controlling the Armstrong, PILOT, is secretly planning to convert the ship's entire human population into mind-controlled cyborgs in order to ensure the survival of mankind from the threat of the Kerak.