Since the death of his mother, 14-year-old Carter Kane has traveled the world with his archaeologist father. Carter's 12-year-old sister, Sadie, lives in London with her grandparents. When Julius and Carter pay their semi-annual visit to England, the three go to the British Museum where the Rosetta Stone is on display. Their father tries to summon Osiris, the Egyptian god of the dead, by writing hieroglyphs on the Rosetta Stone with his wand. But instead of Osiris appearing, the Rosetta Stone explodes, and a fiery being emerges. It conjures a golden sarcophagus around their father, and the sarcophagus sinks into the floor and disappears. The fiery being threatens Sadie and Carter, but disappears when Zia and Desjardins, magicians from the House of Life, arrive. Zia and Desjardins are magicians who are a part of an ancient society that dates back to the time of the pharaohs.
Back at their grandparents' house, Sadie and Carter must answer questions asked by the police about the missing Rosetta Stone. A man dressed in black arrives, and they learn he is their father's brother, their Uncle Amos. He tricks the police and summons a magical boat that transports him, the children and Sadie's cat, Muffin, to his mansion in New York. There, they are introduced to Uncle Amos' unusual pets (a baboon and an albino crocodile) and learn about their own magical heritage. They also learn that their father released several Egyptian gods and goddesses, including Set, the god of chaos and desert storms. Carter believes that to save his father, he must stop Set by the end of "Demon Days," five days that the sky goddess added to the end of the Egyptian year.
When Uncle Amos leaves on a journey to Phoenix, the mansion is destroyed by serpopards (cat-serpent monsters). The Kanes are rescued by Sadie's cat, which is a host for the Egyptian cat goddess, Bast. A "host" can be any living creature that is indwelled by a god. The gods can possess a host, making it do their will, or they can work with their host.
The scorpion goddess pursues the Kanes until Zia opens a portal to the Cairo airport and the headquarters of the House of Life. There they meet the chief lector of the House of Life.
Desjardins is suspicious of the Kanes' connection to the gods because magicians have kept the gods imprisoned for centuries. Sadie and Carter learn that they have become hosts for Isis and Horus, respectively, when their father summoned the gods at the Rosetta Stone. This explains why Sadie has the ability to read hieroglyphs and Carter displays unusual talent in magical combat. The siblings' souls (or bas) regularly leave their bodies while they sleep and travel through the Duat (a supernatural world that exists beneath the physical world), where they witness various occurrences from the past and present. Carter sees Set building a red pyramid inside a desert cave near Phoenix. Set is amassing an army of demons. He hopes to use them to reintroduce chaos to the world with them. Carter also sees Uncle Amos being captured by Set's minions.
When the chief lector of the House of Life dies of old age less than 24 hours after the siblings' arrival, Desjardins becomes chief lector, and at Zia's urging, Sadie and Carter flee for their lives. They open a portal to Paris and find Bast waiting for them. They thought the scorpion goddess had killed Bast.
Sadie and Carter transform into birds and break into Desjardin's Parisian home to find a book containing crucial information about how to defeat Set. After finding the book, they are pursued by an army of fruit bats and several magicians. They escape by teleporting to the Washington Monument, where Sadie's bas meets with the sky goddess, who gives instructions to go to Memphis, Tenn., in search of Thoth, the god of wisdom.
With the Set animal (a monster that shares Set's cunning, strength and evil nature) on their heels, Sadie, Carter and Bast take an airplane to Memphis. (The site of their last portal, the Washington Monument, requires a cool-down period before it can be used again.) The sky goddess warns Sadie's spirit that the Set animal is pursuing them. It follows them from the Washington Monument to the airport, where mortals mistake it for a rabid moose. Bast and Sadie board the plane, and Carter fights the Set animal in the terminal. He traps it in the Duat and hurries to board the plane.
Thoth sends Sadie, Carter and Bast to Elvis Presley's home in Graceland, where they fight shabti (animated clay or wax figures that can appear to be real humans or animals). They survive, and Thoth tells them that to defeat Set, they need to take a boat to the Land of the Dead and convince the jackal-headed god, Anubis, to give them a feather of truth. Anubis asks Sadie if she would let her father die in order to save the world from chaos. She says she would, and Anubis gives her the feather.
Sobek, the crocodile god, mounts an attack. Uncle Amos' albino crocodile appears and distracts Sobek long enough for the Kanes to escape, but Bast is killed. She uses her last shreds of energy to spare her host, Sadie's cat. Uncle Amos also reappears. He had been captured by Set and escaped.
Desjardins catches up with Sadie and Carter. Zia summons a pillar of fire to chase him away, but not before Desjardins summons a giant fiery woman, who continues the pursuit. Carter tells her that huge vats of salsa are filled with human blood, and she gorges herself on salsa until she turns into a cow.
A storm brews in Phoenix, and the end of the Demon Days approaches. As Carter, Sadie, Uncle Amos and Zia travel to Phoenix via transport truck, Zia suggests that Uncle Amos is possessed by Set. She tells Sadie to perform the incantation that will destroy Set, but Sadie refuses.
Together, they storm Set's demon-guarded pyramid, which is nearing completion. Once inside, Set reveals that he did possess Uncle Amos and engages Carter in combat. His father, who hosts Osiris, remains trapped in the sarcophagus at the pyramid's base. Carter taps into Horus' strength to fight Set, but is losing badly. With the help of Isis, Sadie opens a portal between Phoenix and Washington, and transports the entire pyramid away from the desert and Set's source of power.
Weakened, Set is about to be destroyed by Sadie's incantation when she catches a glimpse of the serpent Apophis in the clouds, waiting to use the pyramid as a portal into the world. Sadie chooses to make a deal with Set and destroy the pyramid, killing her father, but saving earth from a chaotic force. Zia's true identity as a shabti is revealed after the fight. The chief lector of the House of Life had hidden the real Zia somewhere safe, as she hosts the goddess Nephthys. Both Carter and Sadie voluntarily release Isis and Horus, a move that convinces Desjardins to leave them alone (at least temporarily).
They meet their parents in the Hall of Judgment, which is in the Duat, and their father reveals that he needed to die to restore Osiris to his throne as the god of the dead. Both believed that releasing the gods was a necessary step to defeat the rising forces of chaos. To show their thankfulness, the gods rebuild Uncle Amos' ruined mansion and resurrect Bast. The Kanes set off looking for other descendants of the pharaohs to join their cause.