According to the United States Census Bureau, Ninety Six has a total area of 1.5 square miles (3.9 km2), all land.

Speculation has led to the mistaken belief that traders estimated it was 96 miles (154 km) from here to the nearest Cherokee settlement of Keowee (it was about 78 miles (126 km)); to a counting of creeks crossing the main road leading from Lexington, South Carolina, to Ninety-Six (a legend proved false); to an interpretation of a Welsh expression, nant-sych, meaning "dry gulch".

No one is able to confirm that European founder Robert Goudey (sic) was Welsh, English, Scottish, or German.

Traders passed on information to each other about landmarks and distances along the Cherokee Path, and sometimes created maps.

One story suggests that a town in this area and a district both became known as "Ninety-Six", likely related to the evolution of traders' references to 9 and 6, the landmark groups of streams.

Using historical accounts and USGS maps, historians have traced the Cherokee Path across present-day Greenwood County, territory that at the time was part of other districts.

[7] Another source suggests the numerical reference was to measuring by Chain, traditional in English parishes.

For a time it was known as "Jews Land" because some prominent Sephardic Jewish families of London bought extensive property there.

On August 1, 1776, American militia forces led by Major Andrew Williamson were ambushed by Cherokee and Loyalists near here in the Battle of Twelve Mile Creek.

More than 4,000 Cherokee warriors had waged war on a long front beginning in June, from modern Tennessee to central South Carolina.

In fall 1776, Virginia, North and South Carolina, and Georgia raised rebel militias to retaliate.

From May 22 to June 18, 1781, Major General Nathanael Greene, with 1,000 Continental Army troops, besieged 550 American Loyalists who were defending Ninety Six.

The Loyalists survived the siege and relocated after the war to Rawdon, Nova Scotia, Canada, with support from the Crown for resettlement.