Annabeth, a demigod and daughter of Athena, is both excited and nervous to be flying in the Argo II, a Greek warship designed and flown by her new friend, Leo, the son of Hephaestus. Along with Jason and Piper — also demigods — and Coach Hedge, a satyr, Annabeth hopes the Roman demigods they're meeting won't kill them. But Annabeth is also excited because she knows that her boyfriend, Percy Jackson, the son of Neptune, is also in the Roman camp.
At first, all goes relatively well. Annabeth and Percy are reunited, and the crew of the Argo II is treated to a Roman banquet. The Greek and Roman demigods speak civilly for the first time in centuries, explaining the quests and trials both camps have had in the past year. Their quests center around Gaea, an ancient earth goddess of immense power, who is reawakening and hoping to destroy the gods and the humans.
The demigods are sure that the Prophecy of the Seven is coming true. In it, seven demigods from Roman and Greek camps must travel to the Doors of Death and fight a battle. Percy had been warned that they must first travel to Rome to find answers before they seek the Doors.
Gaea's allies have captured the Doors of Death and now release ancient foes from Tartarus back onto the earth to try and stop the demigods. A harpy named Ella arrives and repeats another prophecy. This one tells how the Mark of Athena burns in Rome and that twins will kill the angel of death.
Reyna, the head of the Roman camp, talks with Annabeth to learn more about the Greek demigods. Reyna tells her that she's heard lines from Ella's prophecy before, spoken by a son of Athena who was half-crazed from a failed quest. Reyna begins to tell Annabeth what she believes is the source of the animosity between the Greek and Roman demigods, but then explosions ring out across the camp. The Argo II is attacking the Romans.
Before the ship can be blown from the sky, Annabeth and her crew, along with Percy and his friend Frank, manage to get aboard and fly away. Hazel, another Roman demigod, follows them on her horse, Arion. After a scan from Festus, the brains of the Argo II, they decide to land near Salt Lake City to get the parts they need to repair the ship. Leo admits that he fired on the Roman camp but can't explain why. It was as if his actions weren't his own.
When the ship lands, Leo lets Hazel aboard. She acts like she's met him before, although Leo is sure they never have. The demigods split up to find supplies. Frank, Percy and Annabeth go to get tar. Hazel and Leo ride Arion and find the source of celestial bronze in the area. Along the way, Hazel asks Leo if his name is really Sammy. She says he looks so much like a boy she once knew with that name.
Leo assures her that he's always been Leo. Before they locate the celestial bronze, they run into Nemesis, the goddess of revenge. She warns them that the gods of Olympus are being pulled between their Roman and Greek natures, making them rather schizophrenic. She tells Hazel that her brother, Nico, is being kept prisoner and will die in six days unless Hazel and her friends free him.
Nemesis gives Leo a fortune cookie. Inside is the answer to a problem he won't be able to solve. The answer, however, will require a great sacrifice. Nemesis directs them over a hill to the source of celestial bronze. It turns out to be a bronze mirror in the lake. The only problem is that it's Narcissus' mirror, and he won't let them take it because once it's removed, he won't be able to see his reflection. After an elaborate ruse, Leo and Hazel manage to steal the mirror and return to the Argo II.
Back at the ship, Piper is worried about Jason. The Romans had knocked him unconscious before they boarded. She is also afraid of the visions she sees in her charmed knife. One of them shows the Romans rallying to find the Argo II and stop the quest. Another shows Piper, Percy and Jason drowning in a circular room.
Jason finally wakes up as the other demigods return from their errands. Leo quickly repairs the ship, and they set off for Topeka, as Piper had seen the destination in her knife, along with the god Bacchus. Once they land, Percy, Piper and Jason set off to find the god. Percy calls his Pegasus, Blackjack, while Jason calls Tempest, a wind horse. Piper rides with Jason.
When they meet with Bacchus, he gives them information about the twin giants they must face to free Nico. He also says he won't help fight the giants unless he is given a proper tribute. Before he leaves, he tells the demigods to go to Atlanta and find Phorcys, the twins' brother. He might be able to help them.
Gaea's voice rises from the fields around them. Jason and Percy are possessed by eidolons, evil spirits, and are ordered to fight to the death. Jason is knocked unconscious again, but before Percy can kill him, Piper gets Blackjack to knock him out as well. She brings the boys back to the ship where they are given ambrosia, a healing liquid. They reveal what they learned from Bacchus.
Piper realizes the eidolons are still on the ship. When she asks them to reveal themselves, Jason, Percy and Leo all raise their hands. Using her charmspeak, a powerful ability to persuade others to do what she wants, Piper gets the eidolons to leave the ship and promise never to possess another member of the crew again.
In the morning, Percy tells the others about a dream he had of the twin giants. They kept Nico in a large, sealed urn. He had five seeds with him. Hazel explains that these seeds deaden the body's systems so it can survive without food, water and little oxygen, one day at a time. The demigods land in Atlanta.
Percy, Hedge and Frank look for Phorcys at the aquarium. An employee named Kate leads them through a special entrance, explaining that they are VIPs. The demigods suspect she is some kind of monster, but follow her anyway. She takes them into an area hidden from the rest of the tourists. Mythical sea creatures are kept drugged and captive in tanks. Phorcys arrives and explains how he and his sister Keto (Kate) were exiled to Atlanta after supporting the Titans in an ancient war.
Phorcys babbles about Gaea's plan to kill a group of demigods. All but two must be destroyed. A boy and girl must be saved to be offered as a sacrifice in order for Gaea to attain her full power. He also lets it slip that there is a map in Charleston that could help them in Rome. Then he imprisons Percy and Frank in an enchanted tank. They manage to escape with Coach Hedge's help. They flee to the Argo II, pursued by sea monsters. Leo gets the ship in the air, and they travel to Charleston.
Once in South Carolina, Frank, Leo and Jason seek the map in an old museum, while Piper, Annabeth and Hazel seek it by the harbor. There they meet Aphrodite, who offers them tea. She explains that the ancient rift between Romans and Greeks came when the Romans stole the statue of Athena that stood in the Parthenon. They split Athena's personality when they took the god, changing her into Minerva — the goddess of wisdom and crafts — and Bellona — the goddess of war. Athena never forgave the Romans, and throughout the centuries, has sent her children to try to find the statue and restore it to Greece. Annabeth must seek it when they arrive in Rome.
They are interrupted by the arrival of Roman legionnaires. Annabeth throws her knife into the harbor, which alerts Percy to their trouble. He causes a tidal wave to overpower the Romans. They must then save Frank and Leo, who have been shot down over Fort Sumter. The Romans have an army ready for battle, and they are surrounding the fort.
Reyna finds Annabeth and begs her to return to the Roman camp for a trial. If she doesn't, the entire force of the Roman army will go up against Camp Half-blood. Annabeth convinces Reyna to let the seven demigods try to complete their quest. Annabeth and her friends manage to escape, and Leo sails the Argo II out to the ocean, where the Romans are afraid to follow.
Hazel shows Leo one of her memories so he can see why he reminds her of her old boyfriend Sammy. The memory shifts to show an old man Hazel doesn't recognize. Eventually they realize that the man is Sammy and that Leo is his great-grandson. Sammy asks baby Leo to help Hazel if he ever sees her.
Before they can process what they've seen, a giant shrimp-like creature attacks the ship. Leo, Frank and Hazel are swept overboard and taken prisoner by fish centaurs. Once convinced they aren't enemies, the centaurs help the demigods. The demigods promise to free the sea creatures held captive by Phorcys.
The Argo II arrives in the Mediterranean Sea, but before they can continue to Rome, Piper and Jason must face Hercules, who guards the way. He demands they retrieve the remaining horn of the river god, Achelous. If they fail to bring him the horn by sundown, Hercules will kill them.
The demigods find Achelous. Piper tricks Achelous into believing she will become his wife so he'll let Jason go free. Jason calls down lightning to electrify the river and destroy the god. Piper manages to take his horn before he dissolves into the water. They refuse to give the horn to Hercules, instead burying him under an avalanche of food that comes from the horn, which is a cornucopia.
Once back on the boat, they are attacked by Chrysaor, another son of Poseidon, and his army of dolphin-men. Once again, the demigods are able to use deception to defeat their enemy. This time, Percy convinces the dolphin-men that Bacchus, their mortal enemy, has pledged his help to their quest. The dolphin-men flee in terror.
Frank transforms into a giant bear and attacks Chrysaor, forcing him off the boat. The demigods then fill Chrysaor's ship with Diet Coke and sink it as an offering to Bacchus, along with the $6 million of gold and gems aboard.
Once in Rome, the demigods must split up to pursue their different quests. Annabeth seeks to follow the Mark of Athena to her mother's statue. She eventually finds the cavern of Mithras. The spirits who guard it threaten that she may never leave. Annabeth uses her wits to keep herself alive and manages to escape by collapsing the cavern ceiling. She breaks her ankle in the process and must accomplish the rest of her quest in excruciating pain.
Frank, Leo and Hazel search Rome for any sign of Nico, Hazel's brother. They end up in secret tunnels under the Pantheon, an ancient temple. Leo is thrilled to discover the spheres and scrolls of Archimedes, another son of Hephaestus and a brilliant engineer. Before they can leave with their treasures, they are attacked by the eidolons. The spirits take possession of the various machines Archimedes had created and attack Frank and Hazel.
Leo manages to lock himself into an area away from the creatures, but knows he must help his friends. He manages to reassemble one of Archimedes' spheres and uses the special fortune cookie that Nemesis gave him in order to find the code to make it start, even though he knows it will mean he has to make a great sacrifice. He gets the code and uses the sphere to control the other machines. He eventually manages to make the eidolons destroy each other.
Back on the boat, Jason, Piper and Percy decide to strike out in search of Nico. They are led to an ancient silo, a shrine to the nymphs. The grotto has long been abandoned, and the nymphs have been turned to Gaea's side. They start to fill the silo with poisonous water, drowning the demigods as both Piper and Percy have seen in their dreams. As they reach the ceiling, Piper takes out the cornucopia and orders Percy and Jason to think the best thoughts they can. They must sacrifice all their power into the cornucopia. Clean water begins to pour from it, but it still drowns the trio. With her last breath, Piper tells Jason that she loves him.
The water overwhelms them, but then, suddenly, starts to flood out of the grotto. Piper's plan worked. The nymphs have been returned to their former selves as a result of the demigods' willingness to sacrifice their power. Once free of the grotto, the demigods continue their search for the giants who hold Nico prisoner.
The trio finds and battles the giants, managing to briefly destroy them and set Nico free. Giants, however, cannot be destroyed without a god's help. Bacchus arrives, but demands that Jason and Percy fight the giants in the coliseum. They do, but can't fully defeat them until the Argo II brings an explosion. Then Bacchus delivers the deathblow to each giant.
Percy, Piper and Jason climb aboard the ship and discover Leo, Hazel and Frank have also managed to return. They set off in search of Annabeth, who is locked in a battle of wits with her mother's mortal enemy, a giant spider named Arachne. The statue of Athena is suspended by spider silk over a chasm.
Annabeth uses deception, promising Arachne that she'll get her tapestries displayed at Mount Olympus, but first the spider will have to create one additional masterpiece. Annabeth tricks the creature into building a huge model of Chinese handcuffs, then convinces Arachne to look inside for a flaw in the weaving. The spider gets stuck, and Annabeth is free.
The Argo II blasts through the ceiling to rescue her. Arachne falls through the chasm to Tartarus. Leo hauls the statue up into the ship. Percy helps Annabeth to her feet. Suddenly she is dragged toward the chasm because a piece of Arachne's silk has attached to her leg.
They call for help, but their friends can't hear them. Percy swears he will not let Annabeth go again. He and Annabeth plummet to Tartarus. Leo is convinced that this is the sacrifice he had to make for the code in the fortune cookie. The remaining demigods rally themselves to continue the quest to find the Doors of Death. It is the only way they can save their friends Annabeth and Percy.