Sam Gribley, a perceptive and resolute teenager, is the central figure in My Side of the Mountain. Raised in a large family of eleven in New York City, he cherishes his solitude and autonomy. His mother, who formerly worked as a dietician at a children's hospital, and his father, a former sailor now employed at the docks, support Sam's venture into self-sufficient living.

In the wilderness, Sam's closest companions are Frightful, a trained peregrine falcon; Jesse Coon James, a raccoon; and Baron Weasel. These animals become his friends, offering protection and companionship.

During his year in the wild, Sam mostly avoids human contact but does form a few significant friendships. One is Miss Turner, a librarian who helps him find the old farmstead and even gives him a haircut with her library scissors. Another is Bando, a college English professor who gets lost while hiking in the mountains. Bando spends ten days with Sam in the summer and returns for Christmas; he crafts willow whistles and fires clay pots for blueberry jam. Sam also befriends a boy who works at the drugstore, known to Sam as "Mr. Jacket." By the year's end, this boy, whose real name is Tom Sidler, becomes a frequent weekend visitor to the woods.

Other characters include Bill, a kindly old man who teaches Sam to start a fire with flint and steel; ninety-seven-year-old Mrs. Thomas Fielder, who insists Sam pick strawberries for her; the fire warden, curious about Sam's fires; deer poachers and other hunters; Aaron, a hiker from New York who visits the Catskills during Passover; and Matt Spell, a young reporter from a New York newspaper who writes an article about Sam.

The book explores themes of independence versus the need for relationships, the roots of loneliness, critiques society's disregard for privacy, and questions whether individuals can "live in America today and be quietly different." It also highlights the joy and feasibility of living in harmony with nature. Sam's daily activities are inventive and resourceful; he approaches challenges with practical wisdom and determination.