The Son of Neptune begins with Percy Jackson being chased by the Gorgon sisters. They intend to kill Percy to avenge the killing of their sister Medusa by him. Percy manages to escape and stumbles upon Juno, who gives him two options: to carry her to the Caldecott Tunnel and across the little Tiber (although he is warned that after crossing through the river he'll lose the curse of Achilles) or to retreat to the safety of the sea and live a long, happy life.
Percy chooses to carry her, and when he gets to Caldecott Tunnel he meets two other demigods: Hazel Levesque and Frank Zhang. While they cross the river, Percy sees Frank get caught by the Gorgons and controls the river to kill the Monsters. Percy is taken to the head of the camp, a girl named Reyna. He is then made part of the fifth cohort, Frank and Hazel's, and prepares for the night's war games. During the war games Frank and his friends impress everyone with their skills and after the games Mars appears. He claims Frank as his son and sends Percy, Hazel, and Frank on a quest to free Thanatos, the god of Death, who is imprisoned in Alaska.
On the quest, they bump into an old man named Phineas, who is all-knowing and all-seeing. He tells them that he will reveal the location of Thanatos if they capture a harpy named Ella and bring her to him. Before capturing Ella, they learn that she can memorize anything she reads and decide to gamble with Phineas instead. Phineas and Percy will each drink a vial of Gorgon blood, one of which kills while the other heals. Phineas ends up dying and the trio discover the location in Phineas's pocket: Hubbard Glacier.
On the way to Alaska, Hazel reveals that she was actually supposed to be dead but was rescued from the Fields of Asphodel by Nico di Angelo and that seventy years prior to the story she was originally started to wake up Alcyoneus but stopped him from rising the day he was due to escape. Frank learns that he can turn into any animal and is descended from Poseidon as well as Mars. At that point he reveals to Percy and Hazel that his life depends on a piece of firewood that he always keeps. When it burns out, he would die.
When they finally reach the glacier, they find Thanatos in chains. His chains cannot be broken unless melted by the "fire of life", a.k.a Frank's firewood, so Frank started melting the chains as Hazel and Percy attacked Alcyoneus and his ghost legion, respectively. The trio eventually freed Thanatos and managed to drag Alcyoneus across the border into Canada, where Frank kills him.
The trio rushes back to Camp Jupiter, where, with the help of Tyson, Mrs. O'Leary, and the Roman Legion they fend off the Giant Polybotes's army. After seeing the eagle standard , the legion regains their hope and fights with renewed energy. Percy then challenges the giant Polybotes (born to oppose Poseidon) to a duel, as the rest of the camp fights the rest of the monsters. Percy calls to Terminus to help him defeat the giant, as giants can only be defeated by both a god and demigod. Percy eventually beats Polybotes after a battle using the head of Terminus' statue as a weapon. After the battle the legion names Percy as praetor, one of the two leaders of the Roman camp. Nearing the end, the groups of Greek camp demigods inform Percy of their arrival through a video Scroll and Tyson. Percy then tells Hazel and Frank that they can "now meet his other family"