Smyth County, named to honor General Alexander Smyth, was created by an act of Legislature on February 23, 1832. Two-thirds of the 435 sq. miles of new county came from Washington County, and one-third from Wythe County.

The first permanent settlement in Smyth County was the 1747 Royal Oak Survey. The area was renamed Marion effective May 25, 1832, honoring General Francis Marion, "the Swamp Fox" of the Revolutionary War.

During the Civil War, Saltville was attacked twice as one of the main sources of salt during the war. The first raid in October of 1864 was repelled, but in December of 1864, the salt works were destroyed. The railroad and bridges in the county were damaged, and the Thomas Iron Furnace was destroyed. The two-day battle of Marion took place east of the town, near present day exit 47 of I-81.

Branches of the Holston River divide Smyth County into three fertile valley's, an important factor in the development of industry and agriculture. The river was given its present name in honor of Stephen Holston, who settled near Groseclose before 1747. The famous Wilderness Road, also known as the Great Road, and the Stage Road, now traverses Smyth County from the northeast to the southeast as Lee Highway (Route 11).

Other communities developed in the area. Present day Chilhowie first appears on a 1748 survey granted to Col. James Patton, and was called Indian Fields, and later Kilmacronan. the town, known later as the Town House, took its name from a large log house which stood on a hill overlooking the town. This historic house/inn/fort was probably built by Capt. James Thompson about 1770. By 1773 it was a noted landmark in official records. Chilhowie, also once called Greever's Switch, was home of a famous brick factory, the Bonham Apple Orchards, and was the last residence of Madam Russell, a local historic figure, who died here in 1825.

Saltville was referred to as "Big Lick" on the 1748 survey granted Charles Campbell, father of Gen. William Campbell. Known as the "Salt Capital of the Confederacy", Saltville is one of Smyth County's most historic sites. Famous for its production of salt, attraction to various species of animals, discovery of prehistoric animal bones, and the role it played in the Civil War, Saltville has a rich past to draw upon. The Museum of the Middle Appalachians was erected to preserve and expand on the history of Saltville and surrounding areas.

Another community located on Charles Campbell's 1748 survey is currently known as Seven Mile Ford. It obtained its current name as a result of being a river crossing seven miles from the Royal Oak Fort in Marion.

Sugar Grove, located on the South Fork of the Holston River, was first settled in 1753 by Joseph Crockett and his sister-in-law Esther Crockett. Today, on Route 16, near Sugar Grove, the Headquarters of the Mount Rogers National Recreation Area is located, as are the Raccoon Branch and Hurricane Campgrounds.