The book is written as a recording made by the Kane siblings, Carter and Sadie. The story begins when Carter Kane and his father, Julius Kane, go to London to visit Sadie, Carter's sister who lives separately from them. Julius takes them to the British Museum to "study" the Rosetta Stone. But he actually has deeper motives and tries to summon Osiris, the Egyptian god of the Underworld by using the stone as an anchor. It goes wrong when all the other four major gods are brought out and Set, the Egyptian god of storms and chaos, imprisons Julius (he is now a host of Osiris) in a coffin.
Carter and Sadie are taken to Brooklyn by their uncle, Amos. He goes to find Set, leaving the two near-stranger siblings alone with a baboon called Khufu. In the library of the Brooklyn mansion, they begin to discover signs that they are descended from famous pharaohs. Julius' side of the family was descended from Narmer while their dead mother, Ruby, had a family originated from Ramesses the Great. The term is blood of the pharaohs.
Just then, the mansion is attacked by serpent leopards,also known as serpopards. Sadie's cat, Muffin, turns out be the cat goddess Bast. She makes quick work of the serpopards but the three are forced to run when the carriers tails them. They go into Manhattan, which Amos had earlier said had other non-Egyption gods. At the Metropolitan Museum of Art, Bast attempts to have them go in the Duat – a magical realm right underneath the mortal realm. But the goddess of scorpions, Serqet, fights Bast and supposedly overpowers her.
In the museum, Carter and Sadie find Zia Rashid. She is the scribe of the First Nome,the main nome of the House of Life, that had magicians trying to protect people and fight gods. Carter develops a massive crush on Zia in the book. Zia combats Serqet and bans her from her host by using the Seven Ribbons of Hathor spell.
Zia takes the two to the First Nome, where Chief Lector Iskander – the House of Life leader – and Desjardins – the second-in-command – brought up the assumption that they were both hosts of gods. Sadie and Iskander have a talk and the old Chief Lector tells her about the hosts. They were mortals who the gods inhabited so they could leave the Duat and be in the mortal realm.
The next day, the two siblings begin their training. Zia teaches them the concept of casting hieroglyphs to use magic. Carter surprises Sadie and Zia by summoning a combat avatar – it is a magic and Bast used it to fight Serqet – of Horus, the falcon war god. But their training is disrupted when a magician informs Zia that Iskander is dead and Desjardins is next in line for the throne. Sadie creates a portal and they escape to Paris because Desjardins would want to kill them because they are hosts, but not before bringing sphinxes with them. Bast, who is still fine, takes care of them and all of them infiltrate Desjardins' house so they could take a book to fight Set.
At Washington, D.C they are chased by the Set animal, who Carter named Leroy. Carter stays back at the airport to fight it and manages to wound it with his combat avatar. He throws Leroy in his Duat locker-a short opening to the Duat-and manages to catch the airplane to Memphis, Tennessee, where the wisdom god Thoth is.
When they finish Thoth's test, they learn that they were supposed to have a Feather of Truth from the Underworld/Land of the Dead. And they also needed Set's true name, which contained the person's identity and life. Because of Sadie's attraction to Anubis-god of funerals-he gives the Feather of Truth to her. They then continue from New Orleans to Texas, where Carter fights Sobek but is hopelessly outmatched and outclassed even with the combat avatar. Amos saves them but Bast and Sobek are expelled to the Duat.
They go to New Mexico, as Zia wanted Carter there and the earth god Geb told Sadie to. It turns out that Desjardins had known this and a fight occurs. Thanks to Zia's plan, they defeat Sekhmet, the lion goddess of battle, and drive onwards to Arizona. They spot the Red Pyramid, which is Set's main host. When they arrive, Amos collapses and Set reveals he was hosting Amos as well, all along.
Carter merges completely with Horus becomes the eye of the war god. He puts up a good fight but Set's strength grows when dawn approaches and the desert glows. Sadie learns from a dying Zia that Set's secret name is Evil Day. She combines with Isis, the magic goddess inside her, and transports Carter and Sadie along with herself to Washington, D.C. Sadie banishes Set to the Duat, reading the book and using the Feather of Truth along with his secret name.
Just then, Set's servant appears. He is the host of Apophis, the Serpent of Chaos itself. Even though Carter kills the servant, it is Sadie who rubs the picture of the snake in the sky. They come back for Zia, who turns out to be a shabti-a ceramic doll-and urges Carter to find the real Zia Rashid.
They return to Brooklyn House and rebuild the place with magic. Amos leaves for the First Nome to be healed from being possessed by Set. Carter and Sadie are paid a visit by Osiris, who was bonded with their father. They even see the ghost of their mother who was accompaning Julius. The god of the dead gives them his djed amulet to attract other things. The siblings give up Horus and Isis, who vanish away into the Duat but not before preserving a quarter of their power in the amulets Julius had given them a long time ago. Carter and Sadie store the amulets in Carter's Duat locker and put the djed amulet with it. Once kids began to come, they would teach them divine magic or the path of the gods, which involved channeling a god's power.
- Carter Kane: He is fourteen and was a host of Horus. Since he was 8, when his mom died, he traveled with his father, Julius Kane. He is Sadie's older brother. When he is with his sister (Sadie Kane) his magic power grows in strength
- Sadie Kane: She is twelve and was a host of Isis. She loves gum and has lived with her grandparents since the age of six. Most suspect Sadie to be a diviner. When she is with her brother (Carter Kane) her magic grows in strength
- Julius Kane: An Egyptian magician who is a host of Osiris. He is Carter and Sadie Kane's father. His wife, Ruby Kane, died trying to seal away the chaos snake Apophis in Cleopatra's Needle
- Amos Kane: An Egyptian magician who became a partial host of Set. He is Julius Kane's brother, and a former protector of the Kane children. The children find out that he has been Set's host.
- Zia Rashid: An Egyptian magician who is a host of Nephthys.
- Bast: The Egyptian goddess of cats. She becomes the Kane children's protector after Sadie calls for her to defend and help the children.
- Set: The Egyptian god of chaos and evil, who is the main antagonist of book one. His ultimate plot is to, by his birthday, bring about destruction by means of constructing the Red Pyramid, for which the book is named.