In the film, which is set 800 years after the preceding installment Omega III (2019), Maya Onegin (Emma Watson) is cloned and an Omega Supreme is surgically removed from her body. The United Nations Space Command hopes to breed Omegas to study and research on the spaceship USM Solace, using human hosts kidnapped and delivered to them by a group of mercenaries. The Omegas escape their enclosures, while Maya and the mercenaries attempt to escape and destroy the Solace before it reaches its destination, Earth.
Omega Reborn was released on November 26, 2021 and was critically acclaimed. Roger Ebert of the Chicago Sun-Times felt "almost all shots in the movie are there to fill one with wonder", and Desson Thomson of The Washington Post said the film "satisfactorily recycles the great surprises that made the first movie so powerful".
In 3200, 800 years after the events of Omega III, military scientists on the deep space vessel Solace successfully create a clone of Maya Onegin, using DNA from blood samples taken before her death. They extract from her the embryo of an Omega Supreme that had been growing inside her at the time of her death, and raise it to collect its eggs for further use. As an afterthought, the Maya clone, marked by a number "7" lasered onto her arm, is kept alive for further study. As a result of her DNA being mixed with the Omega's during the cloning process, Maya 7 develops enhanced strength and reflexes, acidic blood, and an empathic link with the Omegas, especially the Supreme.
A group of mercenaries led by a man named Mal (Manu Bennett) and consisting of Johnz (Bruce Campbell), crippled Ymir (Elijah Wood), Kala (Anne Hathaway), Chip (Terry Crews), and Ursa (Chloe Grace Moretz), arrive in their ship, the Quantum, delivering several kidnapped humans in stasis. The military led by the still existing Ashford Industries and it's descendant Klaus Ashford (Thomas Brodie-Sangster), scientists use them as hosts for the Omegas, raising several adult Omegas for study. The mercenaries encounter Maya 7, and their youngest member, Ursa, recognizes her name. Ursa attempts to kill Maya 7, fearing she will be used to create new Omegas, but Ursa is too late; the Omegas have already matured and quickly escape their confinement, damaging the ship and forcing most of the crew to abandon vessel, as Dr. Firch (Iain Glen) disappears with many being killed in the process. Klaus Ashford reveals that the Solace's default command in an emergency situation is to return to Earth. Realizing that this will unleash the Omegas on the planet, Maya 8, the mercenaries, Ashford, a marine named Abu Bakhar (Oded Fehr) and a surviving Omega host, Adam (Alexis Denisof), attempt to destroy the Solace and escape on the Quantum.
As the group makes their way through the damaged ship, Maya 7 discovers the meaning of the number lasered on her arm when she stumbles across seven failed clones in the form of hideously malformed Omega/Maya hybrids that are being stored on board, the seventh of which is still alive and begs to be killed. Maya 7 complies, also destroying the other clones as well, before moving to execute Ashford for his part in their creation and his Ashford Industries to take everything of the life of millions, but ultimately she relents.
Eventually, Mal, Kala and Chip are killed by the Omegas. Ursa is shot by Ashford when he betrays the group, but she quickly returns, revealing herself to be an android, one of the few to escape destruction following the passage of laws making them illegal in 2600. Using her abilities to interface with the damaged ship's systems, Ursa sets it on a collision course with Earth, hoping that the Omegas will be destroyed in the crash. As the remaining survivors near the Quantum, Maya 7 is captured by the Omegas. Taken to the the Supreme's chamber, she learns by a captured Dr. Firch that the Omegas has gained a human ability from the mixing of their DNA as well: now possessing a womb, they can give birth to live offspring without the need for eggs and human hosts. The resulting offspring, which bears a mixture of human and Omega traits, recognizes Maya 7 as its mother and brutally kills the Supreme and Dr. Firch as Maya escapes.
Klaus Ashford arrives on board the Quantum and makes one last attempt to betray the others and escape the ship, but he is killed when the Chestburster inside Adam erupts through his head. The others decide Maya is lost and prepare to leave, but Maya 7 arrives just as they launch and successfully makes it aboard. However, the human/Omega hybrid also makes it onto the Quantum, where it kills Bakar and attacks Ursa. Maya 7 confronts the creature, which is calmed by the appearance of its "mother", before killing it by using her own acidic blood to breach a window in the Quantum's hull, causing the creature to be sucked violently through the small opening and into the vacuum of space. The Quantum successfully enters Earth's atmosphere as the Solace explodes over Africa, killing all of the remaining Omegas aboard.
- Emma Watson as Maya Onegin Clone 7, reprising her role from the previous three Omega films. After having sacrificed herself to kill the Omega Supreme gestating inside her in Omega III, Maya has been cloned using blood samples so that the military may extract the Supreme embryo. As a result of the cloning process Maya has been affected by the Omega Supreme's DNA. She has enhanced strength and reflexes, acidic blood, and can sense the presence of the Omegas. Watson also portrayed the failed Maya Onegin Clone 6.
- Chloe Grace Moretz as Ursa Sculdrew, the newest crew member of the Quantum. She recognizes Maya and has knowledge of the Omegas. Ursa is revealed during the course of the film to be a synthetic and helps the surviving crew interface with the Solace.
- Manu Bennett as Mal Jon, captain of the mercenary ship Quantum. Mal brings the Quantum to the Solace in order to sell kidnapped humans in cryostasis to General Rogers. He is romantically involved with Kala.
- Bruce Campbell as Johnz, a mercenary and member of the Quantum's crew. Johnz plays bad jokes and has a short bad temper, and teases Ymir about his handicap.
- Andrew Garfield as Jason Ymir, the Quantum's mechanic. A paraplegic, he uses a motorized wheelchair. Ymir shares a close friendship with Ursa and an antagonistic relationship with Johnz.
- Thomas Brodie-Sangster as Klaus Ashford. Ashford is Ashford Industries heir and current CEO in 3200. He leads the several scientists aboard the Solace involved in cloning Maya and studying the Omegas. After the Omegas escape he joins the lead characters in their attempt to flee the ship. Though not as the same character, Sangster again portrays a character in the Omega series, as Thomas Stryker and his creator David Ashford, Klaus' ancestor.
- Iain Glen as Dr. Jonathan Firth, another of the scientists involved in cloning Maya and studying the Omegas.