The story opens with Buck, a large and powerful St. Bernard-Scotch Collie, living happily in California's Santa Clara Valley as the pet of Judge Miller. He is stolen by the gardener's assistant and sold to fund a gambling addiction. Buck is then shipped to Seattle. Put in a crate, he is unfed and beaten by the "man in the red sweater". When released, he attacks the man but is badly beaten and taught to respect the law of the club. Buck is then sold to a pair of French-Canadian dispatchers from the Canadian government, François and Perrault, who take him with them to the Klondike region of Canada. There they train him as a post office sled dog. From his teammates, he quickly learns to survive cold winter nights and the pack society. A rivalry develops between Buck and the vicious, quarrelsome lead dog, Spitz. Buck eventually beats Spitz in a fight "to the death". Spitz is killed by the pack after his defeat by Buck and Buck eventually becomes the leader of the team.
The team is then sold to a "Scottish half-breed" man working the mail service. The dogs must carry a heavy load to the mining areas, and the journey they make is tiresome and long. One of the team, a morose husky named Dave, becomes sick and eventually has to be shot to end his misery.
Buck's next owners are a trio of stampeders (Hal, Charles, and a woman named Mercedes from the United States), who are inexperienced at surviving in the Northern wilderness. They struggle to control the sled and ignore warnings that the spring melt poses dangers. They overfeed the dogs and starve them when the food runs out. On their journey they meet John Thornton, an experienced outdoorsman, who notices that the dogs have been poorly treated and are in a weakened condition. He warns the trio against crossing the river, but they refuse his advice and order Buck to move on. Exhausted, starving, and sensing the danger ahead, Buck refuses and continues to lie unmoving in the snow. After Buck is beaten by Hal, Thornton recognizes him to be a remarkable dog. Disgusted by the driver's treatment of Buck, Thornton stops Hal from further mistreatment of Buck, by grabbing his arm, then says to Hal, "If you strike that dog again, I will kill you." Thornton then cuts Buck free from his traces, and tells the trio he is keeping him, much to Hal's displeasure. After some argument, the trio leaves and tries to cross the river, but as Thornton warned, the ice gives way and the three fall into the river and drown, along with the sled and neglected dogs.
Buck comes to love and grow devoted to Thornton as he nurses Buck back to health. Buck saves Thornton when he falls into a river. Thornton then takes him on trips to pan for gold. During one such trip, a Skookum Bench King wagers Thornton on Buck's strength and devotion; the dog wins the bet by breaking a half-ton (1,000-pound (450 kg)) sled free of the frozen ground, pulling it 100 yards (91 m) and winning US$1,600 in gold dust for Thornton. The King offers a large sum for possession of Buck, but Thornton has grown fond of him and declines, telling him, "you can go to hell, sir." While Thornton and his friends continue their search for gold, Buck explores the wilderness and socializes with a timber wolf from a local pack. One night, he returns from a short hunt to find that his beloved master and the others in the camp have been killed by a group of Yeehat natives. Buck eventually kills the natives to avenge Thornton, and he then follows the wolf into the forest and answers the call of the wild. At the end of the story, Buck returns each year as the Ghost Dog of the Northland Legend, to mourn at the site of Thornton's death.