London, 1157 A. D. Crusader knights bury one of their own with a jewel resting in his hands. Jump to the present day where the tombs of many other crusaders are discovered beneath London's catacombs.
Dr. Henry Jekyll (Russell Crowe) enters the tunnels and comes across one particular tomb with hieroglyphs, leading him to realize what this means. Through flashbacks, Jekyll tells the story of Princess Ahmanet (Sofia Boutella). She was a cunning warrior who was ready to succeed her father, the Pharaoh Menehptre (Selva Rasalingam), until his second wife gave birth to a boy. Knowing that the boy would be the Pharaoh's new successor, Ahmanet made a pact with Set, the god of death, to sell her soul for a dark power.
Ahmanet murders Menehptre, his wife, and their baby. She prepares to perform a ritual on her lover using a special dagger that would give Set a body of his own, but the Pharaoh's priests stopped Ahmanet and killed her lover. She was mummified alive and had her sarcophagus taken away from Egypt and down a tomb where she could never be found. We move to Mesopotamia (or Iraq) in the present day. Mercenary Nick Morton (Tom Cruise) and his buddy Sergeant Chris Vail (Jake Johnson) are riding toward a village being overrun by insurgents.
Nick wants to go down for some adventure while Vail is strongly against it. They go down there anyway and get shot at. Vail orders an airstrike to take the insurgents out. As the bombs are dropped, a hole opens in the ground, nearly sucking Nick and Vail down there. They discover Ahmanet's tomb.
The guys' superior, Colonel Greenway (Courtney B. Vance), comes to the site in a helicopter and immediately berates the two for running off and doing their own thing, chasing insurgents. Moments later, an archaeologist named Jenny Halsey (Annabelle Wallis) shows up and smacks Nick for stealing a map from her after they shared a night together. After seeing the tomb, Nick, Vail, and Jenny all descend to see what is down there. Jenny notes that there are watcher statues facing inward instead of outward, and there are chains holding the sarcophagus down while submerged in mercury to weaken evil spirits.
Nick shoots a chain, causing the sarcophagus to rise from its holdings. He then sees a vision of Ahmanet calling to him, thanking him for freeing her. A bunch of camel spiders begin crawling down from the walls. Vail shoots at them but he gets bitten in the neck, though Nick claims they are not poisonous. They get back to the surface and bring the sarcophagus up. Everyone rides home in a plane.
Vail starts to act weird as his skin has turned grey and his eyes look discolored. He tries to cut the sarcophagus free from its holdings. Greenway approaches him to stop him, but Vail stabs him twice, killing Greenway. Vail starts moving toward Nick and the other soldiers, forcing Nick to shoot Vail dead. Nick and Jenny go into the cockpit and see a whole flock of crows flying and crashing through the windshield.
The pilots are killed, and the plane starts to go down. Nick gives Jenny a parachute and pulls it so she can get out safely. The plane then crashes with everyone onboard. Nick wakes up in a body bag at a morgue in London. Standing next to him is Vail's ghost, who tells him that they are both cursed.
Jenny is asked to identify the bodies of the deceased but is surprised to see Nick alive. At the crash site, rescue workers find the sarcophagus and Ahmanet's corpse. One man approaches it and is caught off-guard as Ahmanet sucks the life out of him and his partner to regenerate her body. She then uses her powers to turn them into reanimated corpse slaves. Nick and Jenny are in a pub. He goes to the bathroom and sees Vail's ghost talking to him again. He warns Nick that Ahmanet has chosen him for a reason. Nick then runs out of the pub and is cornered in an alley by a whole swarm of rats.
They crawl all over him as he sees Ahmanet crawling toward him, but he is snapped out of this vision by Jenny. She tells Nick what she learned from reading the hieroglyphs on the sarcophagus. She knows about Set's dagger and the jewel that must join it to complete the ritual. Jenny tells Nick about the jewel being buried with the crusaders there in London. Nick and Jenny go to the crusaders' tombs and they uncover the jewel from the crusader's coffin. As they try to leave, they are trapped by Ahmanet and her undead slaves. Nick and Jenny fight off the undead and escape the tomb.
They ride through the woods in a van and are chased by Ahmanet and the undead. An undead slave crashes through the windshield and causes the van to overturn and roll down a hill. Ahmanet tries to get Nick, but she is shot with a hook and is taken down. A whole team of men show up to rescue Nick and Jenny. The two are taken to Prodigium, a facility located beneath the Natural History Museum of London. As Nick walks through the hall, he sees a number of artifacts, including a skull with fangs (Dracula?) and a scaly forearm (Creature from the Black Lagoon??). Nick meets Jekyll, who begins to explain what he knows about Ahmanet and the forces of evil out there.
Their facility is dedicated to uncovering dark forces and containing them. Ahmanet is chained up and is subdued with mercury being pumped through her body. Nick approaches her and listens to her talking about the ritual she attempted to perform on her lover. She tries to sway Nick by saying he would have complete control over death and become a living god if he joined her. Nick returns to Jekyll's office with Jenny.
Jekyll appears to be undergoing a transformation and tries to prevent it using a serum, but Nick grabs the serum, demanding answers. A Prodigium agent pulls Jenny out but leaves Nick inside. Jekyll then turns into his monstrous alter ego, Edward Hyde. He and Nick fight, with Hyde nearly winning until he gets injected with the serum. Meanwhile, Ahmanet summons a camel spider to crawl into the ear of another agent so that he may break her free from her holds. Ahmanet is loose and she takes the dagger and the jewel. Nick and Jenny flee the facility as Ahmanet begins to unleash a sandstorm upon the city.
Nick and Jenny run through the tunnels where they encounter more of Ahmanet's undead slaves. The two fight them again, with Nick crushing or ripping their heads off. They are pushed into the water by an undead but they destroy it. Nick and Jenny swim up for air but Ahmanet grabs Jenny and drags her underwater. Nick fights off more of the undead and tries to save Jenny, but she drowns.
Nick pulls her body out of the water and is confronted by Ahmanet. He attempts to smash the jewel until Ahmanet once again tries to persuade him to join her. Nick holds the dagger out as if to give it to her, but he instead stabs himself with it, now becoming possessed by Set. He battles Ahmanet and gives her the kiss of death to suck the life out of her, reducing her back to a corpse.
Nick then goes over to Jenny and brings her back to life by screaming at her to wake up. He then disappears. Jenny reunites with Jekyll as Ahmanet's body is placed back into a sarcophagus filled with mercury. Jenny wonders what will happen to Nick now that he is technically a monster. Jekyll muses that it took a monster to defeat a monster, and that there is hope for Nick so long as he retains a shred of his humanity.
Somewhere in the desert, Nick has brought Vail back to life. They ride their horses off on another adventure as a sandstorm follows them..