In Skagway in 1900, Jack Thornton announces to a crowded bar that he is going home after striking it rich in the gold fields. However, he loses most of his money gambling first. Then he runs into an old pal, "Shorty" Hoolihan, just released from jail after serving a sentence for reading other people's mail. Shorty tells Jack that the contents of one letter he read is worth a million dollars. It contained a map to a rich gold strike; prospector Martin Blake died before he could stake his claim to it, but the letter was mailed to his son John. Shorty had to eat the map when he was apprehended, but tried to reconstruct it as best he could from memory. His luck changes when he pays $250 for Buck, a savage St. Bernard dog, to keep him from being shot by an arrogant Englishman named Smith. Jack and Shorty head off for the Yukon with the map, Buck and other dogs. Along the way, they rescue Claire Blake from wolves. Her husband is Martin Blake's son and had the original map; he left to look for food and did not return. She refuses to leave without determining John's fate, but Jack drags her away. Sharing the hardships of the trail on their way to Dawson, her initial loathing of Jack gradually melts away. Once they reach Dawson, Jack proposes she join forces with them, as she knows what parts of Shorty's map are wrong. She agrees. However, they still need a stake. Smith bets a thousand dollars against Buck that the dog cannot pull a heavily loaded sled weighing thousand pounds a hundred yards. Buck manages the feat, enabling them to buy what they need. After the trio set out in search of Martin Blake's find, a barely alive John Blake is found and brought in. He talks Smith into backing him and joining him on the trail to the site, but does not trust the Englishman and his two henchmen. The three reach their destination and find it to be all they had hoped. Shorty leaves to file a claim. Jack and Claire wait and eventually acknowledge their love for each other. Buck, in the meantime, feels a strong urge to join a pack of wolves; he frequently leaves to spend time with a female wolf. When Blake and Smith reach the site, Smith has Blake strangled, then holds Jack and Claire at gunpoint. The intruders take the gold they have already gathered and destroy anything that would enable the couple to leave. The villains then leave in their canoe, but it overturns and they drown, weighed down by the stolen gold, within sight of Jack and Claire. Buck finds John Blake, still alive, though in bad shape. They nurse him back to health. Jack wants to keep Claire anyway, but she will not go along. Jack then recommends that John leave to get proper medical attention before the weather makes it impossible. John and Claire leave.
During the filming of Call of the Wild, Clark Gable impregnated Loretta Young, which resulted in Young's hushed-up pregnancy and the birth of their daughter Judy Lewis. The pregnancy was widely assumed to be the result of an affair; however, in 2015, Linda Lewis, Young's daughter-in-law, stated publicly that Young had confided to her before her death that Gable had raped her, and that though the two had flirted on-set, there had been no affair. This was the last film released under the Twentieth Century Pictures' banner before it merged with Fox Film Corporation to create 20th Century-Fox, now renamed 20th Century Studios. Coincidentally, the 2020 adaptation of the novel was the first film released under the 20th Century Studios name.