Charles Pinckney began practising law in Charleston and served in the Revolutionary militia, taking part in the siege of Savannah in 1779. Captured when Charleston fell in 1780, he remained a prisoner until 1781. After the war he served in South Carolina's legislature and the Continental Congress, advocating stronger national powers and secure American navigation of the Mississippi. His older cousin Charles Cotesworth Pinckney was a fellow delegate.

At the Constitutional Convention in 1787, he attended and spoke regularly and submitted a plan of government. His later claim that his draft formed the basis of much of the Constitution is disputed: the version he supplied afterward does not reliably establish what he presented in 1787. He nevertheless made substantial contributions. Like other South Carolina delegates, he defended slaveholding interests and resisted measures that threatened them. He then worked for ratification in his state.

Pinckney served four terms as governor, in 1789–92, 1796–98 and 1806–08, and presided over South Carolina's constitutional convention in 1790. Initially associated with the Federalists, he opposed Jay's Treaty and moved toward Jefferson's Republicans, appealing to upcountry voters against established coastal interests. Elected to the United States Senate in 1798, he helped organise Jefferson's presidential campaign in South Carolina in 1800.

As minister to Spain from 1801 to 1805, he tried unsuccessfully to obtain the Floridas and dealt with the diplomatic consequences of the Louisiana Purchase. Returning home, he supported reapportionment and wider suffrage for white men, changes that expanded political participation while preserving racial exclusion. His final federal service was in the House of Representatives from 1819 to 1821, where he opposed congressional restrictions on slavery during the Missouri controversy. Failing health ended a career that combined nationalism and electoral reform with a persistent defence of slavery.