Percy Jackson, Annabeth Chase, and Thalia Grace get a ride from Mrs. Jackson to Westover Hall, a boarding school in Bar Harbor, Maine, to escort two sibling half-bloods named Nico and Bianca di Angelo that Grover Underwood has found. They are attacked by a manticore named Dr. Thorn. Though Artemis and her hunters arrive to help, Annabeth is captured by Dr. Thorn. Artemis is troubled by the manticore's mention of a "Great Stirring" of monsters, and goes off alone to hunt an Olympus-destroying monster she believes to have finally returned from Tartarus. She sends the half-bloods and Hunters (whose number now includes Bianca di Angelo) to Camp Half-Blood with her brother Apollo.

While there, Nico settles into camp life; Percy and Blackjack save a sea monster Percy nicknames Bessie; and Artemis's lieutenant Zoë Nightshade has mysterious dreams about the goddess being in grave danger. Percy has similar dreams about Annabeth. Both are unable to act, however, until the Oracle (a shriveled mummy) somehow leaves her storage room and delivers the Huntress a prophecy. Chiron and Zoë organize a quest,but Percy is not included because the Hunters refuse to travel with a boy. He successfully sneaks away from camp on Blackjack, though he is almost stopped by Mr. D (Dionysus).

When they arrive in Washington, D.C., Percy notices Dr. Thorn heading into the National Museum of Natural History, and follows him using an invisibility cap. Luke and a man called the General are there, and summon spartoi to hunt the official quest group, who are currently in the National Air and Space Museum nearby. Percy runs to warn them, but they are attacked by the Nemean Lion before they can leave. They flee, and, on the advice of Apollo, travel to Cloudcroft, New Mexico. In Cloudcroft, Grover senses the presence of Pan, who sends the Erymanthian Boar to help them escape the spartoi who have caught up with them. The boar carries them as far as Gila Claw, Arizona and the "junkyardof the gods". After a brief encounter with Ares and Aphrodite, the group enters the junkyard, where Bianca tries to take a cursed statuette for Nico. Her theft awakens a prototype of Talos, and she gives her life to bring it down. The remaining quest members travel to the Hoover Dam, and, after narrowly escaping the spartoi again, arrive in San Francisco.

Once there, Percy seeks out Nereus and learns that the monster Artemis was hunting is Bessie, the monster he saved, who is an ophiotaurus. After a final encounter with Dr. Thorn, Grover heads back to Camp Half-Blood with the ophiotaurus. Zoë, Percy, and Thalia go to find Frederick Chase in the hope that he will help them reach their final destination: Mount Tamalpais, which is the modern location of the Titans' fortress on Mount Othrys. With Mr. Chase's car, they travel to the Garden of Hesperides. Zoë is wounded by the dragon Ladon while they pass through. From the place where Atlas once held up the sky, they see Artemis now doing his job. Seeing Annabeth in chains and learning that "the General" is Zoë's father Atlas, Percy takes the burden from Artemis so his companions can fight the Titan's advance guard. Artemis manages to force Atlas back under his burden, but not before he seriously wounds her lieutenant. Thalia battles Luke, and he falls from a cliff, apparently dead. With the help of Mr. Chase, who arrives in a biplane he has fitted with celestial bronze weaponry, they escape and travel to Olympus. Zoë dies during the trip and is turned into a constellation by the lady Artemis.

During the winter solstice meeting, the gods are finally convinced by Artemis to take action against the Titans. Thalia is also asked by Artemis to become an immortal Huntress, and her acceptance is the only thing that prevents the onset of the Great Prophecy. Percy is told by his father that Luke is somehow not dead, and he and Annabeth return to Camp Half-Blood worried about the future. Before he can relax, however, Percy is forced to explain Bianca's death to Nico. Nico blames Percy, and when a group of spartoi arrive to attack the son ofPoseidon, Nico banishes them to the realm of Hades. Percy realizes Nico must be a son of Hades. Nico runs away, and the only people Percy tells the truth are Annabeth and Grover. They promise to hide this fact from everyone else, especially the Titan's army.