Pinckney received tutoring in London, attended several preparatory schools, and went on to Christ Church College, Oxford, where he heard the lectures of the legal authority Sir William Blackstone and graduated in 1764. Pinckney next pursued legal training at London's Middle Temple and was accepted for admission into the English bar in 1769. He then spent part of a year touring Europe and studying chemistry, military science, and botany under leading authorities.

Late in 1769, Pinckney sailed home and the next year entered practice in South Carolina. His political career began in 1769, when he was elected to the provincial assembly. In 1773 he acted as attorney general for several towns in the colony. By 1775 he had identified with the patriot cause and that year sat in the provincial congress. Then, the next year, he was elected to the local committee of safety and made chairman of a committee that drew up a plan for the interim government of South Carolina.

When hostilities broke out, Pinckney, who had been a royal militia officer since 1769, pursued a full-time military calling. When South Carolina organized its forces in 1775, he joined the First South Carolina Regiment as a captain. He soon rose to the rank of colonel and fought in the South in defense of Charleston and in the North at the Battles of Brandywine, PA, and Germantown, PA. He commanded a regiment in the campaign against the British in the Floridas in 1778 and at the siege of Savannah. When Charleston fell in 1780, he was taken prisoner and held until 1782. The following year, he was discharged as a brevet brigadier general.

After the war, Pinckney resumed his legal practice and the management of estates in the Charleston area but found time to continue his public service, which during the war had included tours in the lower house of the state legislature (1778 and 1782) and the senate (1779).

Pinckney was one of the leaders at the Constitutional Convention. Present at all the sessions, he strongly advocated a powerful national government. His proposal that senators should serve without pay was not adopted, but he exerted influence in such matters as the power of the Senate to ratify treaties and the compromise that was reached concerning abolition of the international slave trade. After the convention, he defended the Constitution in South Carolina.

Under the new government, Pinckney became a devoted Federalist. Between 1789 and 1795 he declined presidential offers to command the U.S. Army and to serve on the Supreme Court and as Secretary of War and Secretary of State. In 1796, however, he accepted the post of Minister to France, but the revolutionary regime there refused to receive him and he was forced to proceed to the Netherlands. The next year, though, he returned to France when he was appointed to a special mission to restore relations with that country. During the ensuing XYZ affair, refusing to pay a bribe suggested by a French agent to facilitate negotiations, he was said to have replied "No! No! Not a sixpence!"

When Pinckney arrived back in the United States in 1798, he found the country preparing for war with France. That year, he was appointed as a major general in command of American forces in the South and served in that capacity until 1800, when the threat of war ended. That year, he represented the Federalists as Vice-Presidential candidate, and in 1804 and 1808 as the Presidential nominee. But he met defeat on all three occasions.

For the rest of his life, Pinckney engaged in legal practice, served at times in the legislature, and engaged in philanthropic activities. He was a charter member of the board of trustees of South Carolina College (later the University of South Carolina), first president of the Charleston Bible Society, and chief executive of the Charleston Library Society. He also gained prominence in the Society of the Cincinnati, an organization of former officers of the War for Independence.

During the later period of his life, Pinckney enjoyed his Belmont estate and Charleston high society. He was twice married; first to Sarah Middleton in 1773 and after her death to Mary Stead in 1786. Survived by three daughters, he died in Charleston in 1825 at the age of 79. He was interred there in the cemetery at St. Michael's Episcopal Church.