Hazel Levasque wishes the Argo II, a boat that can both fly and float, was taking her back to her home at Camp Jupiter. But the camp, a training facility for Roman demigods, such as Hazel, is the last place she and her friends will be going. Instead, they are flying over the Apennine Mountains and being attacked by boulders thrown by mountain gods.
Hazel and five other demigods — Leo, Jason, Frank, Piper and Nico — must find a way to the House of Hades. Buried within this temple, the Doors of Death need to be found so they can rescue their friends Percy and Annabeth from Tartarus. Hazel is thrilled when her horse, Arion, appears below. The horse, which is capable of such high speeds that it can run over water, seems to want to speak with Hazel, so she climbs down the ship's rope ladder.
Arion wants to take her into a distant funnel cloud. She agrees, knowing he wouldn't do anything to purposely hurt her. Inside the cloud, Hazel meets with Hecate, the goddess of magic. Hecate informs her of a pass through the mountains, which the Argo II might be able to use. She also tells Hazel that she must learn to control the Mist — a supernatural veil that separates the real world from the world of myth. Hazel must develop her talent in order to save the quest when it reaches the House of Hades.
Annabeth and Percy, Greek demigods, survive in Tartarus by drinking from the Phlegethon, a river of fire. The flames burn but eventually heal them of the injuries they've received. Annabeth and Percy know they must make it to the Doors of Death if they're ever going to get out of Tartarus, though they don't know where to find them. The good news is that they spy others heading toward the Doors. The bad news is that the others are vampires they fought and killed several years ago. Percy and Annabeth follow the vampires from a distance. The vampires discover the demigods and attack. Fortunately, Bob, a Titan whose memory Percy had erased years ago, protects them. The vampires are defeated, and Bob offers to help them through Tartarus.
Back on the Argo II, dwarves sneak aboard and steal Leo's prized Archimedes sphere. Leo and Jason track the dwarves to Bologna and retrieve the sphere. In exchange for their lives, the dwarves give them an astrolabe and a strange book the dwarves admit belongs to a minor god in Venice. The dwarves also promise to harass the Roman army of demigods marching on Camp Half-blood.
Hazel, her boyfriend, Frank, and her half-brother Nico, take the book Leo found to Venice. The city is crowded with mythical cow creatures. The creatures believe that the demigods are trying to hide their food, so they attack. Their weapon is the emission of a noxious green gas that incapacitates Hazel. Frank shape shifts into a lion and defeats several of the creatures while Nico uses his iron sword to fight them.
Frank and Nico manage to carry Hazel to Triptolemus, a god of agriculture. He turns Nico into a pot of corn and then orders Frank to get him a new python for his chariot before he will consider healing Hazel. Frank must battle with all the katobleps, the giant, poisonous cow-creatures, in order to fulfill his quest. Filled with the power of his father, Mars, Frank singlehandedly slaughters hundreds of the beasts. The battle transforms Frank physically, growing taller and more muscular. As a reward for his bravery, Mars turns one of the corpses into a python that Frank brings to Triptolemus.
Triptolemus heals Hazel and transforms Nico back to himself. He warns them that at the House of Hades they will have to drink from a chalice of poison in order to proceed to the next level of death. The only way to survive the poison is to first eat some barley.
Annabeth tries to send a message to her friends at Camp Half-blood, using the altar at the Hermes shrine. She then asks the oracle Rachel to visit Reyna, the praetor of the Roman demigods. In the note, Annabeth gives Reyna a quest that she hopes will stop the coming war between the Greek and Roman demigods.
Annabeth, Percy and Bob flee the shrine, hoping to escape the Titans who seek them. After picking up a new friend, a kitten that Bob names "Small Bob," they encounter the aria — the curses. When they wound Percy, he is struck by a fate he gave one of his previous attackers. They also reveal Percy's deceit to Bob. Bob is reluctant to help Percy further until he remembers that Nico visited him in Hades and told him to trust Percy. As Percy succumbs to death by gorgon's blood, Bob defeats the curses and rescues him. But the poison remains in Percy's blood.
Jason has a vision in which Rachel, the oracle from Camp Half-blood, meets with Reyna and several other Roman leaders. Rachel gives Reyna Annabeth's note from Tartarus. The note asks Reyna to find the Argo II and help the crew return the revered statue of Athena within the ship to Camp Half-blood. In this way, war between the Greek and Roman demigods might be averted.
Jason and Nico visit Diocletian's palace in Croatia in order to gain a staff that can raise an army of the dead. They will need this ghostly army to help them battle to the Doors of Death. Unfortunately for Nico, the scepter is under the protection of Cupid, the god of love. In order to get the scepter, Nico must admit whom he truly loves: Percy Jackson. Jason tries to convince his friend that neither he nor the other demigods will judge him for his feelings, but Nico is still afraid. Cupid gives the boys the scepter, and they return to the Argo II.
Bob brings Percy and Annabeth to the home of Damasen, a giant doomed to live in Tartarus, and kill a drakon (a snake-like, wingless dragon) every day for eternity. The giant heals Percy from the gorgon's poison and allows the demigods some much-needed protection while they rest. Annabeth begs the giant to come on the quest with them so that he may return to the land of the living, but Damasen refuses.
Khione, the snow goddess, and her two half-brothers attack the Argo II. Khione has joined forces with Gaea, the mother-earth goddess, who is intent on destroying the world. Khione throws Leo overboard because of his ability to light fires. She then freezes the crew of the Argo II, except for Piper. She has promised Piper to her brother Zethes. Before she can be taken prisoner, Piper charm speaks to Festus, the mechanical dragon whose head makes up the masthead. She is able to reawaken the dragon, which then spits out fire, melting Zethes and his brother. Piper, with the power of love inside her, manages to send Khione to the underworld by stabbing her with her dagger, but not before the goddess' wind bomb blows the Argo II dramatically off course. The ship crashes into the ground.
Percy and Annabeth trick the goddess of misery into concealing them within her Death Mist so they can travel undetected to the Doors of Death. Unfortunately, the mist also slowly kills them. They manage to escape misery's attempt to poison them, and then evade the goddess of the dark. They jump into a gateway that leads them to the Mansion of Night, cross Acheron, the river of pain, and reach the heart of Tartarus. They know the Doors of Death are there, somewhere.
Leo manages to slow his plummet to earth by using his Archimedes Sphere. Unfortunately, it breaks from the stress. Leo crashes on an island inhabited by the sorceress Calypso. Although at first annoyed at his arrival, she soon gives him food and new clothes. Leo finds himself falling in love with the beautiful sorceress. The two work together to build a ship that will get Leo off the island, but Calypso must remain. Leo promises to return to her, but she doesn't believe him. Other heroes have promised the same thing, only to abandon her. The encounter with Calypso changes Leo, making him less spastic and more introspective. Leo reunites with the others from the Argo II on the island of Malta, and they set off to find the Doors of Death. The Doors exist in both Tartarus and the mortal world, and the demigods must be there if Percy and Annabeth manage to free the Doors from Tartarus.
Bob leads his friends to the Doors of Death, but his Titan brothers guard them. Bob explains that even if Percy and Annabeth manage to cut the chains Gaea put on the doors and enter the elevator to return to the mortal world, someone must stay in Tartarus and hold the "up" button for 12 minutes. If the button is not pushed for the entire time, the passengers will not complete the trip. Bob doesn't tell them where they will end up. Bob volunteers to stay behind and fight the monsters that will try and stop them from returning to the mortal world. Percy secretly tries to figure out a way to put Annabeth on the elevator and stay behind to help Bob.
Unfortunately, before the chains can be broken, the god Tartarus appears to stop the demigods. Bob attacks the god while Annabeth and Percy cut the chains. Neither will get into the elevator, however, and leave the other behind. Tartarus comes near to killing Bob, but the giant Damasen saves the Titan. As the giant attacks Tartarus, Bob promises to hold the elevator button for Percy and Annabeth. Although heartbroken that this sacrifice will end in Bob's death, Percy and Annabeth get into the elevator. They promise to remember Bob and Damasen to their children as the best Titan and the best giant that ever lived.
Leo has brought a gift back for Frank. It's a pouch made of magical, inflammable material. Frank can put the remaining piece of his life stick in the pouch for safekeeping. Frank has been told that once the stick burns completely, his life will end. Since then, he's been paranoid of fire. He is touched by Leo's thoughtfulness. The demigods find the House of Hades and consume the barley cakes they made following Triptolemus' suggestion. Hazel leads them through the ruins until they come to the chalice of poison Triptolemus also warned them about. The barley antidote works, and the demigods proceed to the next level of death's house.
Farther down, the demigods are separated when the floor crumbles beneath them. Hazel and Leo must forge ahead, while Frank, Nico, Piper and Jason fight the monsters released from the Doors of Death. Nico uses Diocletian's scepter to raise an army of ghosts, but the specters won't follow his orders because he's not a Roman officer. The ghosts won't follow Jason either, even though he is a Roman demigod, because they sense he's become too Greek during his time at Camp Half-blood.
Jason promotes Frank to praetor and commander of the legion. The spirits follow his command and defend the demigods from the monsters' attacks. Hazel and Leo battle Pasiphaë, a sorceress, and a giant named Clytius. Pasiphaë informs them that Percy and Annabeth are on their way up in the Doors of Death, but that Clytius will destroy them as soon as they arrive. The sorceress then recreates the Labyrinth, a maze in which those inside are confronted with deadly peril at every turn. Hazel understands that the maze is actually a deadly illusion, and she summons her new powers over The Mist to change the maze and defeat Pasiphaë.
The Doors of Death appear. When the doors open, Percy and Annabeth spill out, unconscious. Hazel, with the help of the goddess Hecate, manages to keep Clytius from killing them. Frank and the other demigods arrive in time to defeat the giant. Once he is dead, Hecate warns that they must speed their way to Athens to prevent Gaea's army from destroying the world.
The demigods return to the Argo II to find Reyna waiting for them. She must return the statue of Athena to Camp Half-blood quickly, but can't take the ship as the others must sail on to Athens. Nico offers to shadow travel with the Roman leader. Although exhausting, he feels if they travel short distances at a time, he can get Reyna back to America before the Greek and Roman demigods break out into war. The others agree to the plan. Nico and Reyna leave with the statue, while Percy and the other demigods sail on to face the oldest of the gods, Gaea.