Spaniards explored the South Carolina coast as early as 1514, and Hernando DeSoto met the Queen of Cofitachiqui in 1540 when he crossed the central part of the state. Spanish fears of French rivalry were heightened when Huguenots led by Jean Ribaut attempted to settle on what is now Parris Island near Beaufort in 1562. After Ribaut returned to France for reinforcements, the soldiers who were left behind revolted, built themselves a ship, and sailed for France the next year. The horrors of that voyage went beyond eating shoes to cannibalism before an English ship rescued the pitiful remainder of the French attempt to colonize here.

The Spanish built Fort San Felipe on Parris Island in 1566 and made the new settlement there, known as Santa Elena, the capital of La Florida Province. In 1576, under attack from Native Americans, Santa Elena was abandoned, but the fort was rebuilt the next year. The English also posed a threat. A decade later, after Sir Francis Drake had destroyed St. Augustine, the Spanish decided to concentrate their forces there. With the withdrawal from Santa Elena to St. Augustine in 1587, South Carolina was again left to the Native Americans until the English established the first permanent European settlement at Albemarle Point on the Ashley River in 1670.

King Charles II had given Carolina to eight English noblemen, the Lords Proprietors. The proprietors' first settlers included many Barbadians, and South Carolina came to resemble more closely the plantation economy of the West Indies than did the other mainland colonies. By 1708, a majority of the non-native inhabitants were African American slaves. Native Americans, ravaged by diseases against which they had no resistance, last significantly threatened the colony's existence in the Yemassee War of 1715. After the colonists revolted against proprietary rule in 1719, the proprietors' interests were bought out and South Carolina became a royal province.

By the 1750s, rice and indigo had made the planters and merchants of the South Carolina lowcountry the wealthiest men in what would become the United States. Government encouragement of white Protestant settlement in townships in the interior and migration from Pennsylvania, Virginia, and North Carolina were to give the upcountry a different character: smaller farms and a larger percentage of German, Scotch-Irish, and Welsh settlers. By 1790, this part of the state temporarily gave the total population a white majority, but the spread of cotton plantations soon again made African American slaves the majority.

Charlestonians were strong supporters of their rights as Englishmen in the Stamp Act crisis in 1765, and South Carolina would play a significant role when differences escalated into the American Revolution. The Charleston merchant Henry Laurens served as President of the Continental Congress in 1777 and 1778. The first decisive victory of the war was the repulse of a British fleet by patriot defenders in a palmetto log fort on Sullivans Island on June 28, 1776. Over two hundred battles and skirmishes occurred in the State, many of them vicious encounters between South Carolinians who opted for independence and those who chose to remain loyal to King George. Battles at Kings Mountain (1780) and Cowpens (1781) were turning points in the war.

South Carolina became the eighth state to ratify the United States Constitution in 1788, and in 1790 moved its seat of government from Charleston to the new city of Columbia in the state's midlands. South Carolinians played a prominent role in antebellum regional and national politics. Andrew Jackson was born near the North Carolina border but claimed South Carolina as his native state. John C. Calhoun served as secretary of war before becoming vice president of the United States in 1824. Calhoun emerged as the preeminent political theorist of state's rights when South Carolina nullified federal tariffs in 1832. The state thereafter was in the lead in resisting the threat to southern institutions from abolitionists and a stronger federal government and was the first to secede from the Union when it ratified the Ordinance of Secession on December 20, 1860.

The first shots of the Civil War were fired in Charleston Harbor on April 12, 1861. Two days later the federal garrison in Fort Sumter surrendered to Confederate forces. Union troops occupied the sea islands in the Beaufort area in November, beginning the move toward freedom for a few of the state's slaves, but few military engagements occurred within the state's borders until 1865. One-fifth of South Carolina's white males of fighting age were sacrificed to the Confederate cause, and General William Tecumseh Sherman's march through the state at the war's end left a trail of destruction. Poverty would mark the state for generations to come.