Dead Space follows the story of Isacc Clarke, a space engineer and his battle against the necromorphs.
The game takes place in the year 2508, when the USG Ishimura ( a Japanese surname which translates literally to "Stone Village"), a "Planet Cracker" starship, sends out a distress signal to the Concordance Extraction Corporation (CEC) during a mining operation on the planet Aegis VII. The CEC dispatches another ship to investigate, the USG Kellion. As the Kellion attempts to dock with the Ishimura, a guidance system malfunction occurs and the Kellion crashes into the Ishimura's dock. The crew then begins to seek another means of transport. As they explore what appears to be an abandoned ship, they are attacked by grotesque monsters who kill off all but Clarke (who becomes separated), Hammond, and Kendra. Hammond recognizes that many of the ship's systems are failing, thus he and Kendra direct and assist Clarke in fixing them, so as to keep them all alive for rescue.
During these treks, Clarke discovers various text and audio logs scattered throughout the ship and pieces together the events that transpired before his arrival: the ship's captain was actually an agent of the Church of Unitology, a large and influential religious cult. The Ishimura was assigned to retrieve the religion's most valuable relic, the Marker, from Aegis VII, under the guise of an illegal mining operation. Soon after the Marker was extracted and brought to the Ishimura, the civilians, first on the planet colony then the ship, suffered from mass hysteria and violent hallucinations, before subsequently killing each other. The captain cut off traffic and communications between the two sides and later went insane. Dr. Terrance Kyne, the Chief Science Officer, tried to relieve him of duty, only to accidentally kill him in a struggle. An alien organism then began ravaging the colony, infecting the bodies of the dead and turning them into "Necromorphs" - organisms that kill to spread the infestation. It then spread to the Ishimura via a colony shuttle carrying several Necromorphs, which crashed into the docking bay. Though Hammond states that he is unaware of what the Marker is, Kendra confides to Clarke that she believes Hammond is lying. Clarke later encounters his girlfriend Nicole, one of the Ishimura's crew, though they are unable to meet.
With the critical systems repaired, the three are able to launch a beacon, attracting a nearby military ship, the USM Valor. However, the Valor, having picked up an escape pod containing a Necromorph - launched earlier by Hammond - is overrun and crashes into the ship. Hammond then deduces, from the military equipment he finds on board, that the Valor was actually assigned to destroy the Ishimura. The group then decides that they must find a shuttle and escape while they can. Clarke and Hammond retrieve the Valor's power core in order to repair an available shuttle, but Hammond is killed by a Necromorph in the process. Dr. Kyne, one of the few survivors, later contacts Clarke and urges him to return the Marker to Aegis VII, believing that it is a means of restraining the Hive Mind that controls the Necromorphs. After assisting Clarke in loading the Marker onto the shuttle, Kyne is murdered by Kendra, who reveals her position as a government operative ordered to retrieve the Marker for her superiors. She reveals that the Marker is a reverse-engineered copy of an artifact found on Earth, and was placed on Aegis VII by the government to monitor its effects. She then leaves on the shuttle without Clarke, but Nicole arrives and is able to help him recall the shuttle via remote pilot, prompting Kendra to flee in an escape pod.
Clarke takes the shuttle with the Marker back to the colony. This pacifies the Hive Mind, but also disrupts the gravity tethers holding a large portion of the planet several miles off the surface, threatening to destroy the colony. As Clarke attempts to escape, Kendra appears and starts to take the Marker back to the shuttle. She shows Clarke, through a recovered distress transmission, that Nicole committed suicide before they arrived on the Ishimura, and Clarke's visions of her were the Marker's way of attempting to bring itself back to the planet. Clarke makes his way back to the shuttle where Kendra is loading the Marker. Before she can leave, the gigantic Hive Mind kills her, but Clarke is able to defeat it. Leaving the Marker behind, Clarke flies off in the shuttle before the colony is destroyed. As he sets course away from Aegis VII, Clarke removes his helmet and watches Nicole's first transmission again. He is suddenly attacked by a horrific mental vision of Nicole. The screen cuts to black and the game ends.