Ninety Six was established on the frontier in the early 18th century; it was known for a time as "Jews Land" because some prominent Sephardic Jewish families of London bought extensive property there. The Salvador and DaCosta families bought , intending to help some poor Sephardic families to relocate to the New World.
The settlement became the capital city of the Ninety-Six District when it was established in July 1769. Since the late 20th century, the National Park Service operates the Ninety Six National Historic Site at the site of the original settlement and fort.
Ninety Six figured prominently in the Anglo-Cherokee War (1758-1761). It also was a site for southern campaigns of the American Revolutionary War. The first land battle of the revolution south of New England was fought here in 1775. 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 had waged war on a long front beginning in June, from Tennessee to central South Carolina. Francis Salvador, a Sephardic Jewish immigrant from London and a planter, was one of the casualties, the first Jew to be killed fighting with the Patriots in the Revolutionary War.
In 1780 the British fortified the strategically important frontier town with a star fort. From May 22 to June 18, 1781 Major General Nathanael Greene, with 1,000 American Patriot troops, besieged 550 American Loyalists who were defending Ninety Six. General Greene's chief engineer at the siege was the world-renowned Polish hero Colonel Tadeusz Kościuszko, who was wounded at the siege. The American Loyalists survived the siege and relocated after the war to Rawdon, Nova Scotia, Canada, with support from the Crown for resettlement.