Born in Scotland, he received a Masters degree from University of Edinburgh in 1739 . Witherspoon opposed the Jacobite rising of 1745-46 and following the Jacobite victory at the Battle of Falkirk (1746) he was briefly imprisoned at Doune Castle, which had a long-term impact on his health. He became a Church of Scotland (Presbyterian) minister from 1745-1758. From 1758-1768, he was minister of the Laigh kirk, Paisley (Low Kirk). He was prominent within the Church as an Evangelical opponent of the Moderate Party. During his two pastorates he wrote three well-known works on theology, notably the satire "Ecclesiastical Characteristics" (1753) opposing the philosophical influence of Francis Hutcheson. He was awarded a Doctorate of Divinity from the University of St Andrews, Fife.
He later accepted a position to become President and head professor of the small Presbyterian College of New Jersey in Princeton, NJ (later named Princeton University), Witherspoon was a major leader of the early Presbyterian church in America.
Witherspoon's legacy at Princeton is assured as 37 judges, three of whom made it to the U.S. Supreme Court; 10 Cabinet officers; 12 members of the Continental Congress, 28 U.S. senators, and 49 United States congressmen studied under him. One student, Aaron Burr, became Vice President, and another, James Madison, became President.
Witherspoon came to support the American Revolution, joining the Committee of Correspondence and Safety in early 1774. His 1776 sermon "The Dominion of Providence over the Passions of Men" was published in many editions and he was elected to the Continental Congress as part of the New Jersey delegation and, in 1776, voted for the Resolution for Independence.
Witherspoon served in Congress from 1776-1782. He served on over 100 committees, including the board of war and the committee on secret correspondence or foreign affairs and helped draft the Articles of Confederation. He also served twice in the New Jersey Legislature, and strongly supported the adoption of the United States Constitution during the New Jersey ratification debates.
He suffered eye injuries and was blind by 1792. He died in 1794.