- In 1526, Lucas Vásquez de Ayllón founded San Miguel de Guadalupe, the first white European settlement near present-day Georgetown. The Spanish settlement was unsuccessful and failed within a few months.
- The Stono Rebellion was not the first slave revolt in South Carolina. The enslaved Africans that came with the Spanish colonizers revolted in November 1526. It is said that these enslaved Africans either traveled south as winter approached or was helped by the local Native Americans.
- The Parsonage Provincial Library in Charleston, South Carolina, was the first public lending library in the American Colonies. The library was founded in 1698.
- "Flora," the first opera performed in the United States was premiered in Charleston, South Carolina, on February 8, 1735.
- The Charleston Museum is the first museum in America. The museum was founded in 1773 and opened to the public in 1824.
- Built in 1830, the Best Friend of Charleston was a steam-powered railroad locomotive considered to be the first locomotive built entirely within the United States for commercial service. It produced the first locomotive boiler explosion in the United States.
- Founded in 1770 and chartered in 1785, The College of Charleston was the first municipal college in the nation.
- Built on May 6, 1840, the South Caroliniana Library was the first building to be used solely as a college library.
- South Carolina was the first state to secede from the Union. South Carolina was also one of the eleven states to form the Confederate States of America.
- The First South Carolina Volunteer Infantry was the first black unit of the Union Army during the Civil War. The unit was organized in November of 1862.
- Mount Vernon Mills, the first electric textile plant, opened in Columbia in 1893. The mill is now home to the South Carolina State Museum.
- Strom Thurmond was the first United States Senator to be elected to the U.S. Senate through write-in votes.
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