An ancient alien artifact known as the Marker is discovered on the planet Aegis VII by the crew of the mining ship USG Ishimura. Excited by their find, the crew brings the Marker aboard the Ishimura, inadvertently unleashing a malevolent alien force that begins to overwhelm the ship. Soon after the Marker is loaded, crew members start experiencing hallucinations and an inexplicable madness spreads. The ship's security officer, Alissa Vincent, becomes aware of the escalating chaos and tries to maintain order as crew members turn into monstrous creatures known as Necromorphs.

As Alissa and her team attempt to understand and combat the Necromorph outbreak, they realize the true horror and magnitude of what they are up against. Desperate measures are taken to try to contain the infection and find ways to survive the onslaught. Amidst the growing horror, personal sacrifices and backstories emerge, revealing the raw human emotions and dire circumstances faced by the crew. While many succumb to the terrors unleashed, a small group strives to fight back, leading to a tense and chilling series of confrontations with the relentless Necromorphs.