Against a desolate and frigid wilderness, a pack of sled dogs toil on an icy trail, towing a sled that carries a coffin containing the remains of an aristocratic adventurer, struck down by the Wild. As darkness falls, the sled's mushers, Bill and Henry, grow anxious. They are running low on ammunition and a hungry pack of wolves is following them closely. Bill also suspects that a wolf is stealing food from their camp.
Every morning Bill and Henry discover another one of their dogs missing, presumably eaten by the wolf pack. One night, a mysterious she-wolf reveals her self in the firelight. Bill and Henry conclude that she has been roaming on the fringes of the camp and luring their dogs into the wild.
The two mushers and their three remaining dogs continue on the trail, but are attacked by the wolf pack. Bill attempts to shoot down the wolves to save his dogs, but misses and is devoured by the pack. With two hounds left, Henry struggles to fend off the wolves' advances. He builds a fire around himself, but the wolves circle dangerously close. They nearly eat him, but a group of travelers saves Henry before he's consumed.
Meanwhile, the wild wolf pack, starved from famine, splits into smaller groups to scavenge for food. The she-wolf and a gray wolf, One Eye, pair up, becoming mates. They settle in a secluded cave, where the she-wolf gives birth to a litter of pups. All the pups die, save one—White Fang, who grows strong and fierce, learning to hunt and fight on his own and alongside his mother. Together, they take down a ferocious Lynx.
One day, White Fang and the she-wolf come to an Indian camp, where the she-wolf's former master, Gray Beaver, captures them. (Gray Beaver raised the she-wolf, who is actually named Kiche, before she ran away to the wild.) Gray Beaver eventually sells Kiche, but keeps White Fang. The pups of the camp, led by Lip-lip, terrorize White Fang, making him a bitter outcast.
White Fang escapes from Gray Beaver once, returning to the wild. But he's overcome by so much loneliness that he returns to his master, who teaches him to work in the sled and encourages his ferocious behavior. White Fang's nature becomes so brutal that he kills Lip-lip when they encounter each other alone in the forest.
Gray Beaver takes White Fang to Fort Yukon, where he trades animal skins and takes to drinking. One night, drunk, he sells White Fang to Beauty Smith, a monstrous man who transforms White Fang into a vicious and victorious fighting dog. In the ring, White Fang encounters a bulldog, which nearly kills him with a severe bite to the throat. A man named Weedon Scott saves White Fang, taking the canine into his care.
Scott gradually befriends White Fang, who sheds his mistrust of man and becomes devoted to his new master. When Scott is about to leave the Yukon for good, White Fang breaks out of the cabin where he's being held and rushes to Scott's side at the docks. The gesture convinces Scott to take White Fang to his family home in Sierra Vista, California. In the Southland, Scott's family and his sheepdog, Collie, distrust White Fang's wild ways. But White Fang grows into a tamer animal by learning the laws of man and society. He learns not to hunt chickens and not to bristle at human touch, or laughter. White Fang proves himself to be a loving and devoted dog when he uses his bark to alert the Scott family that Weedon has been in a horse riding accident. White proves his loyalty again when he attacks and kills Jim Hall, a convict, who breaks into Scott's home to seek revenge on Scott's father, Judge Scott. Though badly injured, White Fang miraculously survives, gaining enough strength to see the litter of pups that Collie has borne him. Surrounded by his pups and his human family, White Fang becomes a beloved and "Blessed Wolf."