The Sea-Wolf tells the story of a soft, domesticated protagonist — an intellectual man named Humphrey Van Weyden — forced to become tough and self-reliant by exposure to cruelty and brutality. The story starts with him aboard a San Francisco ferry, called Martinez, which collides with another ship in the fog and sinks. He is set adrift in the Bay, eventually being picked up by Wolf Larsen. Larsen is the captain of a seal-hunting schooner, the Ghost. Brutal and cynical, yet also highly intelligent and intellectual, he rules over his ship and terrorizes the crew with the aid of his exceptionally great physical strength. Van Weyden describes him as individualist, hedonist, and materialist. Larsen does not believe in the immortality of the soul; he finds no meaning in his life save for survival and pleasure, and he has come to despise all human life and deny its value. Being interested in someone capable of intellectual disputes, he somewhat takes care of Van Weyden, whom he calls "Hump", while forcing him to become a cabin boy, do menial work, and learn to fight to protect himself from a brutal crew.
A key event in the story is an attempted mutiny against Wolf Larsen by several members of the crew. The organizers of the mutiny are Leach and Johnson. The two were motivated by previous slights by Wolf Larsen: Johnson had previously been beaten severely by Larsen, and Leach had been punched earlier while being forced to become a boat-puller. The first attempt at mutiny involved sending Larsen overboard; however, he manages to climb back onto the ship. Searching for his assailant, he ventures into the sleeping quarters, located beneath the main deck, the only exit being a ladder. Several, at least seven men, take part in the mutiny and attack Larsen. Larsen however, demonstrating his inhuman endurance and strength, manages to fight his way through the crew, climb the ladder with several men hanging off him, and escape relatively unharmed. Van Weyden is promoted as mate, for the original mate had been murdered. Larsen later gets his vengeance by torturing his crew, and constantly claiming that he is going to murder Leach and Johnson at his earliest convenience. He later allows them to be lost to the sea when they attempt to flee on a hunting boat.
During this section, the Ghost picks up another set of castaways, including a young unmarried woman named Maud Brewster. Miss Brewster and Van Weyden had known each other previously, but only as writers. Both Wolf Larsen and Van Weyden immediately feel attraction to her, due to her intelligence and "female delicacy". Van Weyden sees her as his first true love. He strives to protect her from the crew, the horrors of the sea, and Wolf Larsen. As this happens, Wolf Larsen meets his brother Death Larsen, a bitter opponent of his. Wolf kidnapped several of Death's crew and forced them into servitude to fill his own ranks, lost previously during a storm. Larsen attempts to assault Brewster, but is stopped by one of his intense, immobilizing headaches, which allows her and Van Weyden to steal a boat and flee.
The two eventually land on an uninhabited island, heavily populated with seals. They hunt, build shelter and a fire, and survive for several days, using the strength they gained while on the Ghost. The Ghost eventually crashes on the island, with Wolf Larsen the only crew member. As a revenge, Death Larsen had tracked his brother, bribed his crew, destroyed the rigging of the sails, and set Larsen adrift at sea. It is purely by chance that Van Weyden and Miss Brewster meet Larsen again.
Van Weyden obtains all of the weapons including firearms left on the ship, but he cannot bear to murder Larsen, who does not threaten him overtly, although Van Weyden fears that Larsen could attack at any time. Van Weyden and Miss Brewster decide they can repair the ship, but Larsen, who intends to die on the island and take them with him, sabotages any repairs they make. After a headache, Larsen is rendered blind. He feigns paralysis and attempts to murder Van Weyden when he draws within arm's reach but just then has a stroke that leaves him blind and the right side of his body paralyzed. His condition only worsens; he loses usage of his remaining arm, leg, and voice. Miss Brewster and Van Weyden, unable to bring themselves to leave him to rot, care for him. Despite this kindness, he continues his resistance even in his ailing state, setting fire to the mattress of the bunk above him.
Van Weyden finishes repairing the Ghost, and he and Miss Brewster set sail. During a violent storm, Wolf Larsen dies. They give Larsen a burial at sea, an act mirroring an incident Van Weyden witnessed when he was first rescued. The story ends with the two being rescued by an American revenue cutter – after sharing a first kiss at the end of a long and harrowing adventure.
