Two hundred years after Ellen Ripley sacrificed herself on Fiorina 161, military scientists aboard the research vessel USM Auriga successfully clone her from preserved blood samples taken before her death. After seven failed, deformed attempts, the eighth clone—Ripley 8—is viable. The scientists surgically remove the Xenomorph Queen embryo gestating inside her chest, keeping Ripley alive to study her unusual physical traits, including enhanced strength, quick reflexes, and acidic blood resulting from cross-species genetic contamination.

A crew of space pirates aboard the starship Betty—including commander Elgyn, second-in-command Christie, heavy-hitter Johner, mechanic Annalee Call, and paralyzed engineer Vriess—arrives to deliver cargo to the Auriga. Their cargo consists of cryogenically frozen humans kidnapped in deep space, intended by military scientist Dr. Gediman to serve as living incubators for the Queen's freshly laid eggs. While the pirates relax, Call sneaks into Ripley's cell intending to assassinate her to stop the Xenomorph rebirth, only to discover the Queen has already been extracted.

The cloned Xenomorphs quickly demonstrate cunning intellect. Trapped in a reinforced observation pen, two drones murder a third member of their pack, using its boiling acidic blood to burn through the floor deck and escape into the ship's maintenance corridors. The creatures overrun the ship, slaughtering soldiers and scientists while General Perez orders an evacuation before being ambushed and killed. The Auriga initiates an automatic emergency protocol, locking onto its default destination: Earth.

Ripley joins the surviving crew of the Betty, alongside surviving scientist Dr. Wren and host victim Purvis, fighting their way through the infested starship to board the Betty and escape before the Auriga crashes into Earth. Along the way, Ripley discovers the horrifying medical lab containing clones One through Seven, witnessing her own failed, mutated developmental stages. Overcome with grief and horror, she incinerates the living, agonizing seventh clone with a flamethrower.

The group braves a flooded kitchen level, swimming for their lives as agile Xenomorphs pursue them underwater. During a confrontation in an elevator shaft, Dr. Wren shoots Call, revealing her to be an Auton—a synthetic second-generation android equipped with artificial consciousness. Call uses her internal interface ports to hack the Auriga's flight computer, reprogramming the vessel to crash deliberately into the Mojave Desert on Earth rather than a populated hub.

Ripley is dragged down into the alien hive by tentacled floor flooring, coming face to face with the cloned Queen. Due to Ripley's human DNA, the Queen’s reproductive system has mutated, developing a mammalian womb that gives live birth to a grotesque humanoid-alien hybrid called the Newborn. Rejecting the Queen, the Newborn tears its biological mother's head off with a single swipe, recognizing Ripley as its true mother. Ripley flees to the Betty cargo bay just as the ship prepares to decouple.

The Newborn boards the Betty cargo bay, cornering Call. Ripley intervenes, distracting the creature with a maternal embrace. Weeping with sorrow and guilt, Ripley cuts her hand against the monster's claw and slaps her acidic blood onto a thick glass windowpane behind it.

The acid eats a small dime-sized hole through the glass. The explosive decompression of deep space latches onto the Newborn, pulling the creature toward the tiny opening. In a gruesome and agonizing display, the vacuum violently liquifies and pulls the Newborn’s internal organs, tissue, and bones out into space cell by cell while Ripley watches in tears, whispering an apology to the dying beast.

With the creature destroyed, Call seals the breach. The Auriga plummets through the atmosphere and detonates in an enormous fireball across the desert plains. The Betty lands safely in Earth's atmosphere. In the final shot, Ripley and Call sit on the lowered cargo ramp, looking out over the clouds toward the Earth's horizon, with Ripley admitting she feels like a stranger in a world she has never truly known.