Born in Frederick County, Maryland, near Hagerstown, Isaac Shelby was the son of Evan Shelby and Letitia (Cox) Shelby. The family moved to western Virginia in 1772 and ran a trading post. He was a lieutenant in Lord Dunmore's War in 1774. The next year he surveyed land in Kentucky and settled there in 1776. During the American Revolutionary War, Patrick Henry, Governor of Virginia, appointed Shelby to secure provisions for the army on the frontier. He was elected to the Virginia legislature in 1780. He served as a lieutenant, captain, and colonel in the War and fought with distinction, particularly at the Battle of Kings Mountain.
Along with James Williams and Elijah Clarke, Col. Shelby led a force of Overmountain Men from Fort Watauga (near present-day Elizabethton, Tennessee) to victory at the Battle of Musgrove's Mill in South Carolina on August 19, 1780. By securing their defensive patriot position on the banks of the Enoree River, Shelby, Williams, and Clarke were able to defeat a much larger force consisting of two hundred British Loyalists and three hundred British provincial regulars.
On September 26, 1780, a greater number of the Overmountain Men again assembled at Fort Watauga and formed a militia under Col. John Sevier and Col. Shelby. These Patriot troops days later crossed the Appalachians at Roan Mountain and successfully engaged the Ferguson's Loyalists at Kings Mountain, a southern battle recognized as one of the turning points of the American Revolution. In an address before this October 1780 battle, Col. Shelby encouraged his men to fight in frontier fashion: "Let each one of you be his own officer, taking every care you can of yourselves, and availing yourselves of every advantage that chance may throw in your way. If in the woods, shelter yourselves and give them Indian play! Advance from tree to tree, pressing the enemy and killing and disabling all you can."
After the creation of the Southwest Territory and the State of Kentucky during the early 1790s, Isaac Shelby enjoyed an even more prominent Kentucky career. He was chosen governor in 1792 and again in 1812. Between his terms as state executive, he served as sheriff of Lincoln County, Kentucky, from 1796 to 1798. His last significant contribution to the region came in 1818 when he, Andrew Jackson, and others negotiated the "Jackson Purchase," which removed control of the western districts of Kentucky and Tennessee from the Chickasaw Indians. To honor this service, the Tennessee General Assembly named Shelby County (Memphis) for him. He died in Lincoln County, Kentucky, in 1826.