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. When the judge is out of town, assistant gardener Manuel, needing money to pay off gambling debts, steals Buck and sells him to a stranger. Buck is shipped to Seattle where, confined in a crate, is starved and ill-treated. When released, Buck attacks his handler, the "man in the red sweater," who teaches Buck the "law of the club," sufficiently cowing him. The man shows some kindness after Buck stops attacking.

Shortly after, Buck is sold to two French-Canadian dispatchers from the Canadian government, François and Perrault, who take him to Alaska. Buck is trained as a sled dog for the Klondike region of Canada. In addition to Buck, Francois and Perrault add an additional ten dogs to their team (Spitz, Dave, Dolly, Pike, Dub, Billie, Joe, Solleks, Teek, and Koona). Buck's teammates teach him how to survive cold winter nights and about pack society. Over the next several weeks on the trail, a bitter 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, they are given new orders from the Canadian government. They sell their sled team to a "Scotch half-breed" man, who works in the mail service. The dogs must make long, tiring trips, carrying heavy loads to the mining areas. While running the trail, Buck seems to have memories of a canine ancestor who has a short-legged "hairy man" companion. Meanwhile, the weary animals become weak, and the wheel dog, Dave, a morose husky, becomes terminally sick and is eventually shot.

With the dogs too exhausted and foot-sore to continue, the mail-carrier sells the remaining eight dogs, including Buck, to three stampeders from the American Southland (present-day contiguous United States)—a vain woman named Mercedes, her sheepish husband, Charles, and her arrogant brother, Hal. They lack survival skills for the Northern wilderness and struggle to control the sled. The trio ignore others' helpful advice—particularly warnings about the dangerous spring melt. When told her sled is too heavy, Mercedes dumps out crucial supplies in favor of fashion objects. They foolishly create a team of 14 dogs, believing they will travel faster. The dogs are overfed and over-worked, then are starved when food runs low. Most of the dogs die on the trail, leaving only Buck and four other dogs when they pull into the White River.

They meet John Thornton, an experienced outdoorsman, who notices the dogs' poor, weakened condition. The trio ignores Thornton's warnings about crossing the ice and press onward. Exhausted, starving, and sensing danger ahead, Buck refuses to continue. After Hal beats Buck, Thornton, disgusted by the Hal's treatment, hits him and cuts Buck free. The trio leaves and cross the river with the four remaining dogs. The ice breaks and the dogs and humans (along with their sled) fall into the river and drown.

As Thornton nurses Buck back to health, Buck grows to love him. Buck saves Thornton when he 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 Buck's strength and devotion. Buck pulls a sled with a half-ton (1,000-pound (450 kg)) load of flour, breaking it free from the frozen ground, dragging 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 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 to search for a fabled Lost Cabin. Once they locate a suitable gold find, the dogs have nothing to do. Buck has more ancestor-memories of being with the primitive "hairy man." While Thornton and his two friends pan gold, Buck hears the call of the wild, explores the wilderness, and socializes with a Northwestern wolf from a local pack. However, Buck does not join the wolves and returns to Thornton. Buck repeatedly goes back and forth between Thornton and the wild. Returning to the campsite one day, he finds Hans, Pete, and Thornton have been murdered by Native-American Yeehats. Enraged, Buck kills several natives to avenge Thornton, then realizes he no longer has any human ties. He goes looking for his wild brother and encounters a hostile wolf pack. He fights them and wins, then discovers that the lone wolf he had socialized with is a pack member. Buck follows the pack into the forest and answers the call of the wild.

The legend of Buck spreads among other Native Americans as the "Ghost Dog" of the Northland (Alaska and northwestern Canada). Each year, on the anniversary of his attack on the Yeehats, Buck returns to the former campsite where he was last with Thornton, Hans, and Pete, to mourn their deaths. Every winter, leading the wolf-pack, Buck wreaks vengeance on the Yeehats, "as he sings a song of the younger world, which is the song of the pack."