Witherspoon took an active political role in the war of Independence.

As was previously mentioned, Witherspoon was an early proponent of America's involvement in the Revolutionary War. Witherspoon joined the New Jersey Correspondence and Safety Commission in early 1774 to promote the American Revolution. Witherspoon presided over the Somerset Correspondence Committee from 1775 to 1776. He was elected to the Continental Congress as a member of the New Jersey delegation, and his 1776 address, "The Dominion of Interest Over Men's Passions," was published in numerous versions.

He served as a representative of the Continental Congress from 1776 to 1779 and once more from 1780 to 1782. He was also a member of two different provincial assemblies. He was named a congressional lieutenant in the National Assembly and cast a vote in favor of passing the Virginia Resolution of Independence in July 1776. He typically said that the nation was "not only ripe for measures, but also at risk of rot for seeking it" in answer to criticisms that it wasn't yet ready for independence.

John Witherspoon's participation in the Articles of Confederation in the first person is an intriguing detail. American Constitution. To host the Continental Congress for four months while the official rooms were being rebuilt, he even opened one of his university's halls.