The main character is a Nicoleño girl named Won-a-pa-lei, whose secret name is Karana. She has a brother named Ramo and a sister named Ulape. Her people live in a village called Ghalas-at and the tribe survives by gathering roots and fishing.
One day, a ship of Russian fur hunters and their Creole and Aleut workers led by Captain Orlov arrive and persuade the Nicoleños to let them hunt sea otter in exchange for other goods. However, the Russians attempt to swindle the islanders by leaving without paying. When they are confronted by Karana's father Chief Chowig, a battle breaks out. Karana's father and many other men in the tribe die in battle against the well-armed Russians.
Later, the "replacement chief" Chief Kimki leaves the island on a canoe for new land in the East. Eventually, he sends a "giant canoe" to bring his people to the mainland even though he himself does not return. The white missionaries come to Karana's village and tell them to pack their goods and go to the ship. Karana's brother Ramo runs off to retrieve his fishing spear. Although Karana urges the captain to wait for Ramo to return, the ship must leave before a storm approaches. Despite restraint, Karana jumps off the ship and swims to shore and the ship departs without them.
While awaiting the return of the ship, Ramo is brutally killed by a pack of feral dogs. Alone on the island, Karana takes on traditionally male tasks, such as hunting, making spears, and building canoes to survive. She vows to avenge her brother's death and kills several of the dogs, but has a change of heart when she encounters the leader of the pack. She tames him and names him Rontu.
Over time, Karana makes a life for herself, even successfully hunting a giant devilfish (a massive octopus or squid) with Rontu. She builds a home made of whale bones and stocks a cave with provisions in case the Aleuts come back, so she can hide from them. She also tames some birds and an otter, named Mon-a-nee, while feeling a close kinship to the animals (the only inhabitants of the island beside herself).
One summer, the Aleuts return and Karana takes refuge in the cave. She observes the Aleuts closely and realizes that a girl named Tutok takes care of the domestic duties including getting water from the pool near Karana's cave. Fearful of being discovered, Karana goes out only at night, yet the curious girl stalks Karana, and the two meet. Karana and Tutok exchange gifts and she realizes how lonely she has been. The next day, Karana sees the ship with Tutok departing. Sadly, she returns to her house and starts rebuilding.
More time passes, and Rontu dies. Karana soon finds a young dog that looks like Rontu and takes him in naming him Rontu-Aru. One day, Karana sees the sails of a ship, but it moors off-shore and leaves. Two years later in the spring, the boat returns. Karana dresses in her finest attire, a dress of cormorant feathers, and waits on the shore for the boat. Her rescuers make a dress for her, as they believe her dress of cormorant feathers is not appropriate for the mainland. She does not like the dress, but Karana realizes that it is part of her new life. The ship takes Karana, Rontu-Aru, and her two birds to the mission in Santa Barbara, California. There, Father Gonzales tells her that the ship that had taken her tribe away had sunk before it could return to the Island of the Blue Dolphins for her.
