Two hundred years after the events of Alien 3, military scientists on the outer space vessel USM Auriga create a clone of Ellen Ripley using DNA from blood samples taken before her death. They extract the embryo of an Alien queen that had been growing inside her at the time of her death, raise it, and collect its eggs for further use. (It is implied that Ripley's actions in the previous two movies effectively wiped out all the aliens.)
The Ripley clone is kept alive for further study. As a result of her DNA being mixed with the Alien's during the cloning process, she develops enhanced strength and reflexes, acidic blood, and an empathic link with the Aliens. A group of mercenaries, Elgyn, Johner, Christie, Vriess, Hillard, and Call, arrive in their ship, the Betty, delivering several kidnapped humans in stasis.
The military scientists use the kidnapped humans as hosts for the Aliens, raising several adult Aliens for study. The Betty crew soon encounter Ripley. Call recognizes her name and tries to kill her, believing she may be used to create more Aliens. Call is too late; the Aliens have already matured and quickly escape confinement, damaging the Auriga and killing those crew members who do not manage to evacuate.
Military scientist Dr. Wren reveals that the ship's default command in an emergency is to return to Earth. Realizing this will unleash the Aliens on Earth, Ripley, the mercenaries, Wren, a Marine named DiStefano, and surviving Alien host Purvis decide to head for the Betty and use it to destroy the Auriga. As the group make their way through the damaged ship, Elgyn, Hillard, and Christie are killed by Aliens.
Call is revealed to be an android after Wren betrays the group. Using her ability to interface with the Auriga's systems, she sets it on a collision course with Earth, hoping to destroy the Aliens in the crash. Wren takes Call hostage, demanding that she abort the collision. Purvis attacks Wren and forces his head to his chest just as the Alien embryo he is carrying bursts through his ribcage, causing it to go through Wren's head and kill him.
Ripley discovers that the Alien queen has gained a human ability from her DNA as well: now possessing a womb, it can give birth to live offspring without the need for eggs and human hosts. The resulting newborn, bearing a mixture of human and Alien traits, recognizes Ripley as its mother and kills the Alien queen and Dr. Gediman.
Ripley and the surviving mercenaries make their way to the Betty. As they launch, the newborn hybrid attacks Call and kills DiStefano. Ripley kills it by using her own acidic blood to burn a hole through a viewpane, causing the creature to be sucked violently through the hole and into the vacuum of space. The survivors escape in the Betty as the Auriga collides with Earth.