The Big Sky by A. B. Guthrie Jr. is a coming-of-age story of a young man, Boone Caudill, who leaves his family and his Kentucky home in 1830 for the unknown adventures of the West. The novel follows Boone's journey as he makes friends, becomes employed by a shipping company, heads further into the West, falls in love, betrays his friend and love, returns to Kentucky, and ultimately leaves for the West once more.

Early on in his journey, Boone befriends Jim Deakins, and the two travel together—supporting one another, working together, and causing mischief. Their friendship represents the in-between stage of adolescence in which the innocence and playfulness of childhood still exists but is met with the seriousness and mystery of adulthood.

As the young men make their way towards Blackfoot territory, they are attacked several times by indigenous tribes, who are protecting their lands from white colonizers. The description of the attacks in the novel seem to be set up to be sympathetic toward the white man and his colonial actions. However, if one uses critical thinking and empathy, it is easy to understand that the tribes are attempting to stop an invading force from stealing their homelands and bringing sickness and death with them as they force their way further into native lands. The novel is certainly reflective of the Manifest Destiny narrative that attempted to justify white colonialism.

Upon meeting Teal Eye, a Blackfoot woman sailing with Boone and Jim on the river boat back toward Blackfoot country, Boone realizes that he desires her. Several years later, Boone, now an adult, is determined to meet Teal Eye again in her home territory with the hopes of marrying her. Boone speaks of this intent to marry Teal Eye as a challenge to be won. His behaviors are reflective of misogynistic colonial attitudes towards women, particularly toward native women, whom white men often viewed as prizes or trophies to be won. Boone further reveals his misogyny after his son is born with red hair, the color of Jim's hair, and he suspects Jim and Teal Eye of having an affair. Rather than speaking to either of them about his concerns, Boone chooses to try to catch the two in an affair. When he sees Jim trying to console Teal Eye on the blindness of her newborn child, Boone takes this comfort as proof of an affair and, without warning, shoots and kills Jim. Only later, after leaving Teal Eye and traveling back to Kentucky, does Boone discover that red hair is common in children in his family and that Teal Eye and Jim were not having an affair. Boone realizes his enormous mistakes far too late, and his life takes a serious downward turn as he plunges into a deep depression.

As farmers begin to move out West in larger and larger numbers, Boone becomes less enamored with the wild adventures of the west, and the novel ends with him feeling lost and confused. The Big Sky emphasizes the fleeting nature of youth, the ways in which misogyny destroys friendships and romances, and the lack of true meaning in a life rooted in white colonialism.