Lewisburg is named after Andrew Lewis. In 1751 Lewis, as a young surveyor, established a camp near the spring behind the present courthouse. This spring has been known as the Lewis Spring since that time. During Pontiac's Rebellion in 1763, Native Americans completely destroyed two of the early European settlements in Greenbrier County, killing the men and carrying off the women and children. This raid virtually eliminated all of the earliest settlers in the county. The Native Americans were primarily Shawnees, and (according to undocumented tradition) were led by the famous leader Hokoleskwa, or Cornstalk.
By 1770 a fortified encampment called Fort Savannah was established at the Lewis Spring. In 1774, Governor Dunmore of Virginia instructed then-Colonel Andrew Lewis to gather "willing and able men" to go to the great Kanawha River and stand against the Native American forces that were attacking the Greenbrier Valley. In what became known as Lord Dunmore's War, over 1,490 men were assembled, some at Fort Pitt at present-day Pittsburgh, and others at Fort Union, on the site of present-day Lewisburg. These recruits included Lewis’s brother Charles, and others which history books refer to as one of the most remarkable assemblages of frontier leaders in American history. Thirteen were men of political and military distinction. Lewis's army marched down the New and Kanawha Rivers to the Ohio River, where they intended to cross over and invade the Ohio Country, which was the home of the Shawnees. The Native Americans, led by Cornstalk, attempted to cut them off at the mouth of the Kanawha, where they fought an inconclusive battle that came to be known as the Battle of Point Pleasant.
Lewisburg was formally established in 1782 by an act of the Virginia General Assembly.
To accommodate Virginians west of the mountains, several Virginia courts sat in Lewisburg, where Patrick Henry once successfully defended a client accused of murder. The town and the surrounding farms prospered and a number of spas and resort hotels were established at some of the outlying mineral springs.
During the Civil War a number of engagements were fought in and around Lewisburg. Several of the present buildings in town were used as hospitals and barracks by both sides in this conflict, and bullet marks can still be seen in some today. The Virginia Supreme Court library, which was located in Lewisburg and served as the Greenbrier County Library until 2008, was used as a hospital and has preserved a section of wall with soldiers' graffiti.
In 1978, a area in the heart of Lewisburg was designated a National Register Historic District.