Boone had little formal education, but he did learn the skills of a woodsmen early in life. By age 12 his sharp hunter's eye and skill with a rifle helped keep his family well provided with wild game. In 1756 Boone married Rebecca Bryan, a pioneer woman with great courage and patience. He spent most of the next ten years hunting and farming to feed his family. In 1769 a trader and old friend, John Findley, visited Boone's cabin. Findley was looking for an overland route to Kentucky and needed a skilled woodsman to guide him. In 1769 Boone, Findley and five men traveled along wilderness trails and through the Cumberland gap in the Appalachian mountains into Kentucky. They found a "hunter's paradise" filled with buffalo, deer, wild turkey and meadows ideal for farming. Boone vowed to return with his family one day.

In 1775 Boone and 30 other woodsmen were hired to improve the trails between the Carolinas and the west. The resulting route reached into the heart of Kentucky and became known as the "Wilderness Road." That same year Boone built a fort and village called Boonesborough in Kentucky, and moved his family over the Wilderness Trail to their new home.

Boone had numerous encounters with the native people of Kentucky during the Revolutionary War. In 1776, Shawnee warriors kidnapped his daughter and two other girls. Two days later Boone caught up with the Indians and through surprise attack rescued the girls. In 1778, he was captured by another band of Shawnee. Boone learned that the tribe was planning an attack on Boonesborough. He negotiated a settlement with Chief Blackfish of the Shawnee, preventing the attack. The Indians admired their captive for his skill as a hunter and woodsman and adopted him into their tribe as a son of Blackfish. He escaped when he learned the Shawnee, at the instigation of the British, were planning another attach on Boonesborough. The settlement was reinforced and provisioned in preparation for the assault. When British soldiers and the Indians attacked, Boonesborough withstood a ten-day siege and Chief Blackfish and the British finally withdrew.

After the Revolutionary War, Boone worked as a surveyor along the Ohio River and settled for a time in Kanawha County, Virginia (now West Virginia). In 1792, Kentucky was admitted into the Union as the 15th state. Litigation arose that questioned many settlers' title to their lands. Boone lost all his property due to lack of clear title. In 1799, he followed his son, Daniel Morgan Boone, to Missouri which was then under the dominion of Spain. Traveling by canoe, he and his family paddled down the Ohio River to St. Louis.