Little Tree is an orphaned boy who relocates to the Tennessee mountains to live with his Cherokee grandparents. He approaches his new environment with intense curiosity, eager to learn woodland survival and his family's whiskey-making trade. Socially inexperienced, he often interprets the harsh prejudices of outsiders literally, assuming goodwill where none exists. He actively works to develop his "spirit mind" to match his grandparents' level of spiritual understanding.

Granpa is an older man of Cherokee descent who operates a covert whiskey still in the mountains. He serves as Little Tree's primary teacher for outdoor survival, emphasizing a harsh but practical philosophy he calls "The Way." He actively distrusts government authority and mainstream society, preferring the autonomy of the wilderness. He involves Little Tree directly in his work, granting the boy a half-share of his whiskey mark.

Granma provides the academic and spiritual foundation for Little Tree's education. She reads William Shakespeare and historical texts aloud to the family, encouraging her grandson to memorize dictionary words. She teaches the concept of the "body mind" versus the "spirit mind," urging Little Tree to develop empathy and inner awareness.

Willow John is an eighty-year-old friend of the family who lives across the settlement. He communicates almost entirely through his eyes rather than spoken words. He forms an immediate, quiet connection with Little Tree after the boy sneaks a bullfrog into his pocket during a sermon.

Pine Billy is a regular visitor to the mountain cabin who brings stories from the outside world. He has a severe tobacco addiction and often attempts to enter essay contests to win more of it. His lack of formal schooling frequently leads him into strange misunderstandings with city dwellers.

Mr. Wine is an itinerant clock repairman with a surname the family cannot pronounce. He visits regularly to teach Little Tree mathematics and personal values. He maintains a playful teaching style, deliberately pretending to misplace his glasses so his young student can practice helping him.

The Reverend runs the state orphanage with severe discipline. He views Little Tree's Cherokee heritage with open disdain and refuses to recognize his parents' marriage as legitimate. He isolates the boy from the rest of the children and actively excludes him from adoption opportunities.

Wilburn is a boy residing in the orphanage who suffers from the emotional toll of repeatedly being passed over by prospective parents. He forms a bond with Little Tree, who uses his spiritual training to sense Wilburn's hidden grief and offer quiet companionship.

Mr. Slick is a city-based whiskey trader attempting to muscle in on the family's territory. He has no understanding of the wilderness, making him highly vulnerable to the harsh terrain and local wildlife. He expects to easily intimidate the mountain residents but grossly underestimates their environmental advantage.

Mr. Chunk works alongside Mr. Slick in the city whiskey trade. He travels into the mountains expecting a simple territorial takeover but immediately falls victim to poison ivy and panic at standard animal noises. His ignorance of nature leaves him entirely at the mercy of the locals.