Part One of the novel shows two men, Henry and Bill, struggling to bring the corpse of Lord Alfred back to civilization. It is a time of famine, and they are low on food; also, they have little ammunition. Thus, they are in a desperate situation because they are being pursued by a pack of famished wolves. As the novel begins, they have six sled dogs, but one night, they notice that there are seven dogs to be fed. Strangely, the next morning, there are only five dogs to be fed. As a result, they become suspicious, and finally they notice a she-wolf who comes to the camp at night and lures the dogs away.
When the men have only two dogs left, Bill decides to shoot the she-wolf, but he is killed himself by the famished wolf pack. Thus Henry is left alone — with only two dogs and no ammunition — and after days of traveling, covering only a short distance each day, he is forced to build a fire to surround himself and protect himself from the wolves. When he awakens in the morning, he realizes immediately that his supply of wood is gone, and he cannot go out and search for some more. He resigns himself, therefore, to the inevitable, but he is finally rescued by a group of men who are also out in the wild.
Part Two of the novel shifts the narrative perspective to that of the she-wolf. After the famine is over, the wolf pack separates, and the she-wolf and three males travel together, until one of the wolves, "One Eye," kills the other two. The she-wolf and One Eye travel together, then, until it is time for her to settle down to give birth to her cubs. Another famine comes upon the land when the cubs are still young, and all of the cubs die — except one: a gray wolf cub. This gray wolf is the strongest and the most adventuresome of all the litter. Yet early in his life, he learns how to snare food and along with this ability, he learns the lesson of the wilderness — that is, "eat or be eaten, kill or be killed."
In Part Three, the cub and its mother wander into an Indian camp, where the mother is recognized by an Indian named Gray Beaver; she answers immediately to the call of "Kiche," and the little gray cub is promptly named White Fang. In the Indian camp, the cub has to learn how to function in the presence of the Indians, and he must also learn how to protect himself against the other puppies. When his mother is taken from him, he attempts to follow her, but he is severely beaten by Gray Beaver, and thus he quickly learns another lesson — to obey the "man-god." When Gray Beaver goes to the nearest fort to sell his furs, he takes White Fang with him. There at the fort, White Fang becomes famous for his ferocious ability to kill other dogs, and he is sought after by a vicious, ugly man named, ironically, Beauty Smith, who, by using trickery and alcohol, is able to trick Gray Beaver into selling White Fang to him. White Fang is treated terribly by this cruel man; he is constantly forced into bloody fights with other dogs so that Smith can win bets. But during one fight with a bulldog, White Fang is at the point of being killed when a man named Weedon Scott, a person of distinction and authority, interferes and stops the fight. Furthermore, Scott pays off Beauty Smith and threatens to have him jailed. Scott then takes White Fang with him.
Under the protection and patience and compassion of Weedon Scott, White Fang gradually learns to appreciate a human being, and ultimately he comes to possess a love and affection for Scott.
When Weeden Scott has to return to his home in the Southland (California), he at first intends to leave White Fang behind. White Fang, however, escapes and sneaks aboard the ship. Scott, therefore, chooses to take the dog along. The novel ends by showing how White Fang learns to exist as a domesticated animal. Ultimately, White Fang wins the affection of Scott's family because of his extreme intelligence (for example, he leads some men to help his injured master) and also because of his performing an act of bravery by risking his life to save Judge Scott from being murdered.