The Kellion arrives at the outskirts of Aegis VII,but they crash-land aboard the Ishimura due to a malfunction. Isaac Clarke,Kendra Daniels,Zach Hammond,& Aiden Chen investigate the Ishimura while Hailey Johnston stays behind. The Crew has been attacked the mutated humans corpse,The Necromorphs & Chen was killed. Clarke was separated from Hammond & Daniels. They begun to find out what caused that outbreak. Clarke went back to the Kellion where the Necromorphs damage the singularity core,causing the ship to explode,killing Johnston.
Hammond was attacked by the mutated Chen,but manage to seal him in an escape pod,jettison him into space. While Clarke was ambushed by the Mutated Captain,who killed by Terrence Kyne,but he manage to kill him exploring & repairing the damaged Ishimura,Isaac briefly reunited with his girlfriend,Nicole & meets Elizabeth Cross,who searching for her lover,Jan Temple & try to kill the giant Necromorph called the Leviathan,who trying to poison the oxygen supply. Isaac discovers the presence of the fanatical Church of Unitology,a cult that led to deaths of his Unitology parents & The Marker,a mysterious icon of Unitology,which apparently caused an outbreak.
Isaac was encountered by Challus Mercer,whose goal is to initiate a Convergence Event & created a powerful Necromorph,the Hunter. Isaac quickly escapes. After he took down the Leviathan,Isaac launches an emergency beacon crafted by Temple in the mining bay,the signal is tracked by USM Valor,but they succumb to the Marker's influence,having picked up Chen's pod,causing the Valor to crash.
While Isaac & Hammond recovers the singularity core & fix the shuttle Hammond,They soon learned that the Valor has already been contacted by someone & orders to destroy the ship at all costs. The Mutated Chen attacks Hammond,who sacrificed himself to kill him. Isaac escapes the Valor with the core. He meets Kyne,who tells him & Daniels to return the Marker to stop outbreak & putting an enormous Necromorph,the Hive Mind to rest.
While helping Kyne recover the Marker,Isaac manage to kill the Hunter & re-encounters with Mercer,who kills Temple before being crushed to death by Necromorph Growths. After Isaac loads the Marker,Kyne was fatally shot by Daniels,who reveals herself to be an Agent sent by the EarthGov to collect the Marker & was one who contacted the Valor. Before she can flee,Isaac reunites with Nicole and recall the shuttle remotely & use it to fly to the surface of Aegis VII.
After they successfully return the Marker to the planet,Daniels,who has flee to the escape pod,held Nicole captive and shows Isaac a video log of Nicole committing Suicide to avoid becoming a Necromorph. The Nicole that Isaac was working for turned out to be Cross,who hallucinates Isaac as Temple. Cross refuses to help Daniels take the Marker off & was killed. Daniels tries to escape,but gets killed by the Hive Mind. Isaac manage to kill it before escaping aboard the shuttle,leaving the Marker as the Ishimura's power fails & its payload crashes onto the planet's surface.
While resting,The exhausted Isaac was engulfed by a bright light and ended in an unknown area.