In the preface to Never Cry Wolf, Mowat mentions that he originally planned to give wolves only a minor role in the book, focusing instead on government bureaucracy's mismanagement and misdirection of conservation efforts. Although his book does highlight bureaucratic absurdities and a lack of vision, its primary focus is on advocating for the protection of wild wolves—both from the unintentional pressures of a developing society and the deliberately harmful actions of self-righteous bureaucrats.

Mowat recounts his own journey in the book. At the outset, he suspects that the government officials who send him to the Northwest Territories lack an understanding of the practicalities of living in the far north. Despite this, Mowat initially shares their misconceptions about wolves. Tasked with assessing the wolves' impact on the declining caribou population, Mowat is initially inclined to believe that wolves are the primary cause of the herds' dwindling numbers. However, as Never Cry Wolf progresses, Mowat realizes that much of what people commonly believe about wolves and their supposed viciousness is untrue.

The wolf family members play crucial roles in the book, prompting Mowat to reconsider the definitions of "civilized" and "wild." Mowat observes so much "humanness" in these wolves that he replaces their scientific names with human ones: George, Angeline, and Albert. As he learns about the structure of the wolf family and the care they take in raising their young, he discovers deep bonds of affection and loyalty within this species.

Mowat also learns that wolves have never posed a threat to humans; instead, humans have been the primary threat to wolves. Humans have devastated the caribou population but have blamed wolves for the decline, ignoring the fact that wolves primarily eat mice, not caribou. Furthermore, when wolves do hunt caribou, they target only the sick and weak.

Besides Mowat and his wolf family, Never Cry Wolf introduces Ootek and Mike, Eskimos living in the Keewatin Barrens. Among the two, Ootek has a special connection to the wolves because he is a shaman, or wise man, with Amarok, the Wolf, as his personal totem. Ootek is not only a skilled naturalist, knowledgeable about arctic animals, but he also has special abilities, including understanding the language of wolves.

At the conclusion of Never Cry Wolf, Mowat reveals that Predator Control officers from the Canadian Wildlife Service were sent to the den of George, Angeline, Albert, and their pups with poisoned bait. The book ends with a powerful plea for the preservation of wildlife.