Wyeth grew up on a farm in New England. He studied at the Massachusetts Normal Arts School and attended classes taught by illustrators Eric Pape and Charles W. Reed. During 1902-04 he studied with the great illustrator Howard Pyle, in Wilmington, Delaware. Pyle was his teacher and idol.
Because Wyeth wanted to paint western scenes, he accepted a commission from Scribner's and the Saturday Evening Post and then traveled in the west to gain first hand knowledge of his subject. On trips to the western United States, he worked as a ranch hand in Colorado and rode mail routes in New Mexico and Arizona.
In 1906 Wyeth and Carolyn Brenneman Bockius were married in the Wilmington Unitarian church. They made their home in nearby Chadd's Ford, Pennsylvania. The focus of his painting soon shifted to the land and people of the region in which he lived. In 1911, with a commission from Charles Scribner's Sons to illustrate a new edition of R. L. Stevenson's Treasure Island, Wyeth began the work upon which his fame would rest.
The Wyeths were members of the First Unitarian Society of Wilmington. According to his soon Andrew, N.C. Wyeth approached his art with a religious spirit and called his Chadd's Ford studio "my church."
The Unitarian Laymen's League commissioned Wyeth in 1922 to illustrate a book on the parables of Jesus. Six paintings were completed by the next year and published in the Boston Traveler. Ultimately ten of an originally proposed twenty were published in 1931 as The Parables of Jesus.
At the time of his death in October 1945, N.C. Wyeth was one of America's best loved illustrators.