Shortly after U.S. Army General Anthony Wayne's significant victory at the Battle of Fallen Timbers in 1794 during the Northwest Indian War, the area began to be called Waynesborough.

General Wayne's well-known popularity with Pennsylvanians is suspected to have helped contribute to this naming.

The town maintained a steady stream of visitors primarily due to its position on Three Notch'd Road, which connected Staunton to the west with Charlottesville and Richmond to the east.

Additionally, a railroad tunnel was constructed through Rockfish Gap a short time before the Civil War began.

On March 2, 1865, Waynesboro was the site of the last battle of the Civil War for the Confederate Lt. General Jubal A.

The Battle of Waynesboro lasted twenty minutes, was a complete victory for George Armstrong Custer, and was a final blow for the Confederate Army in the Shenandoah Valley.

During and after the war, casualties from the nearby Valley Campaign and other battles were buried in Ridgeview Cemetery where the Waynesboro Confederate Monument lists and commemorates their names and states.

The transportation advantages coming from the Iron Cross fueled great hopes for economic development.

An opera house, a wide boulevard called Commerce Avenue, and the upscale Hotel Brunswick were built there.

An important difference between the two was that, unlike Basic City, Waynesboro had implemented restrictive laws banning the sale of alcohol.

Effects of the Panic of 1896 abruptly dried up the boomtown investment in Basic City; grand plans for more hotels and manufacturing complexes were scuttled.

Since 1924, Waynesboro has made numerous territorial acquisitions from areas of Augusta County through annexation and officially became an independent city in 1948.

The DuPont plant was later sold to Koch Industries as part of the subsidiary company Invista.

In January 2019, the plant was again sold to Chinese luxury apparel firm Shandong Ruyi Group and rebranded as The Lycra Company.

A General Electric site on the northeast side, which made relays and later computer printers, was also a substantial employer.

The Blue Ridge Parkway, Skyline Drive, and the Appalachian Trail are fewer than 5 miles (8.0 km) from Waynesboro.

The city is served by two freight rail lines, owned by Norfolk Southern and CSX.

The intersection of the two lines is known as "The Iron Cross", a historically significant symbol of the city's economic growth.