The Lost Hero uses concepts from ancient Greek and Roman mythology in a modern setting. The story is narrated by Jason Grace, then Piper McLean, then Leo Valdez repeatedly, each character telling two chapters at a time. Jason is a boy who suffers from amnesia. He wakes up on a bus not remembering anything from his past, even who he was, and he was sitting next toPiper, a girl claiming to be his girlfriend, and a boy, Leo Valdez, who claims to be his best friend. In a field trip to the Grand Canyon, storm spirits attack the three while their supervising teacher, Coach Gleeson Hedge, reveals himself to be a satyr, and fights for their lives. Jason surprises himself by using a sword disguised as a coin to fight off the spirits, and Coach Hedge is captured while defending them. At the height of the battle, two pegasi land next to them carrying strangers: Annabeth and a boy with a tattoo of a rainbow named Butch, a son of Iris. Annabeth is angry because she had a vision that she would find a clue to her missing boyfriend, Percy Jackson, at the Grand Canyon. She was told to look for the "one with the missing shoe." Jason, who has lost a shoe in the battle, has no memories of his own identity, let alone Percy Jackson's whereabouts. Jason, Piper and Leo are informed that they are demigods (children of a god and a mortal) and are taken back to Camp Half-Blood where they meet other demigod children like themselves. There, Leo is revealed as a son of Hephaestus, Piper as a daughter of Aphrodite, and Jason as a son of Zeus and the brother of Thalia. He remembers his sister while seeing a picture of her in Cabin One. After scarcely 24 hours of learning about their previously hidden identities, the three receive an urgent quest to rescue Hera, queen of the gods, who was captured by unnamed forces.

The three friends set off on the back of a giant robotic dragon, Festus (which in Latin means "happy") on a cross-country quest to save Hera and Piper's father from the clutches of Enceladus. Their enemies are under orders from Gaea to reawaken her and overthrow the Olympian gods by pulling up their original roots in Greece. On their way, Jason, Piper and Leo meet Boreas the North Wind (who lives in the Château Frontenac), a trio of cyclopes, the evil enchantress Medea, King Midas, a pack of werewolves and Lycaon and the very unhelpful Lord of the Winds, Aeolus. In the end the heroes and their friends, the Hunters of Artemis, manage to save both Piper's father and Hera, whose godly energies were being used to raise the giant Porphyrion. They temporarily stall Gaea's plans, but they will have to face the giants again. With part of his memory returned, Jason realizes that he is a hero from a Roman counterpart to Camp Half-Blood somewhere near San Francisco, and that Hera has switched him with the Greek hero Percy Jackson, who is now at the Roman camp with no memory of his life at Camp Half-Blood. Both Jason and Percy had to let the Greek and Roman camps know of each others' existence, so the Roman and Greek demigods must unite to provide the prophesied group of seven heroes who will defeat the giants along with the gods. Jason, Piper, Leo, and Annabeth have to find the Roman camp and convince them to help.