The story opens in 1897 with Buck, a powerful 140-pound St. Bernard–Scotch Collie mix, happily living in California's Santa Clara Valley as the pampered pet of Judge Miller and his family. However, one night, when Judge Miller is out of town, assistant gardener Manuel, in desperate need of money to retire his gambling debts, steals Buck and sells him to a stranger at College Park station for a large amount of cash. Buck is shipped to Seattle. Confined in a crate, he is starved and ill-treated. When released, Buck attacks his overseer, the "man in the red sweater", but this man teaches Buck the "law of the club", hitting Buck until he is sufficiently cowed (although the man shows some kindness after Buck stops attacking). Shortly afterward, the man in the red sweater sells Buck to two French-Canadian dispatchers from the Canadian government, François and Perrault, who take him to Alaska. They train him as a sled dog, and drive him through the Klondike region of Canada. From his teammates, he quickly learns to adapt to survive cold winter nights and the pack society. A rivalry develops between Buck and the lead dog, Spitz, a vicious and quarrelsome white husky. Buck eventually kills Spitz in a fight and becomes the lead dog.
When François and Perrault complete the round-trip of the Yukon Trail in record time—returning to Skagway with their dispatches—and are given new orders from the Canadian government, their team is then sold to a "Scotch half-breed" man, who is also working the mail service. The dogs must make long, tiring trips, carrying heavy loads to the mining areas. During this run of the trail, Buck seems to have memories of his canine ancestor hanging out with a short-legged "hairy man". Meanwhile, the weary dogs become weak, and the wheel dog, Dave, a morose husky, becomes terminally sick and is eventually shot.
With too few dogs to continue, the mail-carrier sells the remaining three dogs, including Buck, to a trio of stampeders from the American Southland (present-day contiguous United States)—a spoiled woman named Mercedes, her sheepish husband Charles, and her arrogant brother Hal. They are inexperienced at surviving in the Northern wilderness, and struggle to control the sled, ignoring helpful advice from others—in particular, the warnings that the spring melt poses dangers. When Mercedes is told her sled is too heavy, she dumps out crucial supplies in favor of fashion objects. They also foolishly create a team of 14 dogs, erroneously thinking they can go faster with more dogs. They overfeed the over-worked dogs and then are forced to starve them when the food supply becomes low. Most dogs on the team die from either weakness, neglect, or sickness—leaving only five dogs when they pull into White River.
There, they meet John Thornton, an experienced outdoorsman, who notices the dogs' poor and weakened condition. Ignoring Thornton's advice, the trio crosses the ice. Exhausted, starving, and sensing the danger ahead, Buck refuses to continue and lies unmoving in the snow. After Hal beats Buck, Thornton, disgusted by the driver's treatment of Buck, hits Hal with the butt of his ax and cuts Buck free from his traces. Unable to cross Thornton, the trio leaves and tries to cross the river with the four dogs remaining, but as Thornton warned, the ice breaks and the dogs and humans (along with their sled) fall into the river and drown.
Buck comes to love and grows devoted to Thornton as he nurses Buck back to health. He saves Thornton when the man falls into a river. After Thornton takes him on trips to pan for gold, a bonanza king (someone who struck it rich in the gold fields), named Mr. Matthewson, wagers Thornton on the dog's strength and devotion. Buck wins the bet for Thornton by breaking a sled holding a half-ton (1,000-pound (450 kg)) load of flour free of the frozen ground, pulling it 100 yards (91 m) and winning Thornton US$1,600 in gold dust. A "king of the Skookum Benches" offers a large sum to buy Buck, but Thornton has grown fond of him and declines.
Using his winnings, Thornton retires his debts but elects to continue searching for gold with friends Pete and Hans—sledding Buck and six other dogs—looking for a fabled Lost Cabin. Once at a suitable gold find, the dogs have nothing to do—and Buck has more ancestor-memories of hanging out with the primitive "hairy man". While Thornton and his two friends are panning in a campsite, Buck hears the call of the wild, explores the wilderness, and socializes with a Northwestern wolf from a local pack. However, Buck decides not to join the wolves and elects to return to Thornton. He repeatedly goes back and forth between Thornton and the wild. When returning to the campsite after strategically killing a bull moose, he finds Hans and Pete murdered, then sees Thornton has suffered the same fate—at the hands of a group of Native-American Yeehats. Enraged, Buck kills several of the natives to avenge Thornton, and he then realizes that he has no ties to humans and the law of club and fang, and goes to find his wild brother. He encounters a hostile pack of wolves and fights them. Buck wins the fight, then finds that the same wolf he had socialized with was in the pack he fought. Buck then follows the wolf and its pack into the forest and answers the call of the wild.
The legend of Buck is spread among other Native Americans as the "Ghost Dog" of the Northland (Alaska and northwestern Canada). Buck comes out of the backwoods once a year on the anniversary of his attack on the Yeehats, at the former campsite where he was last with Thornton, Hans, and Pete, in order to mourn their deaths—while each winter he heads the wolf-pack, wreaking vengeance on the Yeehats, "as he sings a song of the younger world, which is the song of the pack."