Carter and his father Julius arrive in London for a rare visitation day with Sadie. Outside the Fausts' flat, Julius has a tense confrontation with a mysterious man named Amos, who warns him against his planned actions. Julius takes the children to Cleopatra's Needle, where he reveals it is connected to their mother's death. At the Thames, Carter and Sadie glimpse two watching figures - a man with a forked beard and a girl in blue robes. Julius hurries them to the British Museum for what he claims will be a private tour.
At the British Museum, Julius uses a curved wand to inscribe glowing hieroglyphs on the Rosetta Stone, attempting to summon Osiris. The Stone explodes, releasing a fiery figure who traps Julius in a golden sarcophagus that sinks through the floor. The fiery man - later revealed as Set - turns on the children but is repelled by Carter's amulet. Two magicians burst through the wall: the man with the forked beard (Desjardins) and the girl in blue (Zia). Carter and Sadie pass out as the magicians decide whether to destroy them.
Sadie is separated from Carter and locked in the museum curator's office. A police inspector interrogates her but dismisses her account of the supernatural events. From her window, Sadie spots Amos watching the house, though the police claim he phoned from New York. The inspector tries to manipulate Sadie by claiming Carter has already cooperated, but she refuses to turn against her father or brother.
Amos appears at the Fausts' flat and magically influences the inspector to deport both children. He reveals he is Julius's brother - their Uncle Amos - and insists they must come with him to Brooklyn for safety. Despite Sadie's protests, Gran and Gramps reluctantly agree. Amos draws a hieroglyph on the window and summons an Egyptian reed boat at the quayside. Sadie takes her cat Muffin and, along with Carter, boards the boat for a journey to New York.
The reed boat travels impossibly fast through the Duat, arriving in New York within minutes. Amos leads them to a massive limestone mansion perched atop a warehouse in Brooklyn - the headquarters of the Twenty-first Nome. Inside the Great Room stands a thirty-foot statue of Thoth. Amos introduces them to Khufu, a baboon in a Lakers jersey who serves as a house companion. The children discover their rooms are locked, making them feel like prisoners, but Carter reassures Sadie they need to trust Amos for now.
Carter wakes from a ba vision of Set in Phoenix, where the fiery god is planning to build a temple and unleash a devastating storm. Over breakfast on the terrace, alongside Philip of Macedonia the albino crocodile, Amos explains that Julius was attempting to summon Osiris but accidentally released five gods. He reveals their family's ancient magical heritage, that both parents were magicians of the House of Life, and that Carter and Sadie were separated to prevent their combined powers from attracting dangerous attention. Amos leaves for Phoenix to investigate, jumping off the terrace and vanishing.
Sadie uses the ha-di spell to blast open the library doors. Inside they find Dad's workbag containing a painted box with magical implements, including a wax shabti named Doughboy. The siblings discover a scroll titled Blood of the Pharaohs listing their family name, and an illustration of the five children of Nut. Carter identifies Set as the god of chaos and determines the Demon Days begin in two days. A crash upstairs sends them running - serpopard monsters have found the mansion.
Two serpopard monsters attack the mansion, battling Philip of Macedonia who sacrifices himself by pulling them into the East River. When they return and break through the magical wards, Sadie orders Muffin to protect them. The cat transforms into a woman in a leopard-skin jumpsuit - Bast, the cat goddess - who slices the serpopards to sand with twin knives. Bast urges them to flee, saying worse is coming, and asks Sadie to open a portal through the Duat.
Bast explains she made a deal with Julius to protect Sadie in cat form. They flee the burning mansion, pursued by four copper carriers bearing a sedan chair from the Duat. Bast steals a Lexus and they race across the Williamsburg Bridge. The carriers follow with supernatural speed. Bast reveals that Set's magic is stronger than hers and that she can only assume human form because of Sadie's call for help.
At the Central Park obelisk, Bast uses combat magic - a twenty-foot green holographic cat warrior - to destroy the carriers while Sadie attempts to open a portal. The scorpion goddess Serqet arrives with thousands of scorpions. Bast orders them to flee to the Metropolitan Museum and find a temple. She stays behind to fight Serqet, knowing she may not survive. Carter and Sadie run for the museum.
Carter and Sadie flee through the Egyptian wing of the Metropolitan Museum, pursued by Serqet's scorpions. They collide with Zia Rashid, the young magician from the British Museum. Zia disarms Carter, demands to know about Amos, and leads them to the Temple of Dendur. She places protective shabti and prepares to open a portal at noon while defending them from Serqet.
Zia battles Serqet using fire magic and the Seven Ribbons of Hathor, temporarily subduing the goddess and freeing her human host. When Serqet's spirit begins re-forming as a giant scorpion, they plunge through the sand portal. They emerge in Cairo airport. Zia explains they're above the ruins of ancient Heliopolis and leads them underground to the First Nome - the oldest branch of the House of Life.
Carter crosses a chasm on a plank, deflecting magical daggers with his sword. A ba spirit in the form of a bird with a human face greets him as 'good king.' They enter the vast underground city of the First Nome, passing through markets, over rivers of tiger fish, and past chambers of child initiates scrying in bowls of oil. Zia brings them to the Hall of Ages to meet the Chief Lector.
In the magnificent Hall of Ages, they pass through millennia of Egyptian history displayed as holographic memories. They meet Chief Lector Iskandar, a two-thousand-year-old magician born during Cleopatra's reign, and his deputy Desjardins. The children tell their story while instinctively concealing certain details. Desjardins wants them executed, but Iskandar overrules him, allowing Zia to test them. Carter senses Iskandar recognises something about him connected to the ancient pharaoh Nectanebo.
Sadie sneaks to the Hall of Ages at night, drawn to the golden images of the Age of the Gods. She enters a vision of Osiris's birthday feast, where she sees Set trick Osiris into a golden coffin and trap him. She watches Isis flee as a bird, momentarily becoming Isis herself. Iskandar pulls her from the vision, saving her life. In a private conversation, he reveals he knew her mother, speaks of Ruby's gift of divination, and tells Sadie she and Carter have a difficult path ahead. He also encounters a handsome boy in black robes - Anubis.
Zia trains Carter and Sadie in scroll magic at the First Nome, then takes them to the ruins of Luxor for a duel. She reveals their family descends from both Narmer and Ramesses the Great, making them prime candidates for hosting gods. During the duel, Sadie transforms her staff into a lion, and Carter summons a falcon warrior avatar. Zia is shaken by this evidence of divine hosting. News arrives that Iskandar has died in his sleep. Zia warns that Desjardins will order their execution and tells them to flee through the Luxor obelisk.
Carter reveals his ba vision of Amos being captured by Set in a trap. The siblings escape through the Luxor obelisk to Paris, where Bast rescues them from pursuing sphinx ghosts. Bast explains they are 'godlings' - hosts for Horus and Isis respectively. Carter directly communicates with Horus for the first time. Bast reveals their mother died protecting Julius from a magical blast at Cleopatra's Needle, sacrificing her life rather than accepting Bast's help. They break into Desjardins' mansion to steal a book by Thoth that may help defeat Set.
Carter and Sadie transform into birds to infiltrate Desjardins' library. With Doughboy's help, Carter finds The Book of Thoth but triggers a trap that unleashes thousands of fruit bats. They flee as falcons while Desjardins' guards pursue them. They reunite with Bast at the Louvre pyramid, where Sadie opens a portal just before sunset on the first Demon Day. French magicians accuse Bast of abandoning her post and endangering everyone. They emerge at the Washington Monument.
Stranded at the Washington Monument, the group rests and discusses strategy. Carter and Sadie compare their experiences and begin to bond. Bast reluctantly admits she was imprisoned with a creature of chaos and that their mother's final act sealed that gate. Sadie falls asleep and her ba visits the sky goddess Nut, who lives in a floating luxury flat above the city. Nut provides plane tickets to Memphis, Tennessee, advises seeking Thoth, and asks Sadie to deliver a love letter to Geb. She warns that Set's minion is approaching.
Sadie's ba visits Nut in her sky home. The sky goddess explains the history of Ra's exile and her eternal separation from Geb. She advises that Set, despite being evil, is still her son and part of the divine balance, and that defeating him may not be as straightforward as expected. She directs them to find Thoth in Memphis, Tennessee, and warns that Set's forces are closing in on the Washington Monument.