Motivated at least partly by the impact of British economic restrictions on his business, Clymer early adopted the Revolutionary cause and was one of the first to recommend independence. He attended patriotic meetings, served on the Pennsylvania council of safety, and in 1773 headed a committee that forced the resignation of Philadelphia tea consignees appointed by Britain under the Tea Act. Inevitably, in light of his economic background, he channeled his energies into financial matters. In 1775-76 he acted as one of the first two Continental treasurers, even personally underwriting the war by exchanging all his own specie for Continental currency.

In the Continental Congress (1776-77 and 1780-82) the quiet and unassuming Clymer rarely spoke in debate but made his mark in committee efforts, especially those pertaining to commerce, finance, and military affairs. During the War for Independence, he also served on a series of commissions that conducted important field investigations. In December 1776, when Congress fled from Philadelphia to Baltimore, he and George Walton and Robert Morris remained behind to carry on congressional business. Within a year, after their victory at the Battle of Brandywine, Pa. (September 11, 1777), British troops advancing on Philadelphia detoured for the purpose of vandalizing Clymer's home in Chester County about 25 miles outside the city. His wife and children hid nearby in the woods.

After a brief retirement following his last term in the Continental Congress, Clymer was reelected for the years 1784-88 to the Pennsylvania legislature, where he had also served part time in 1780-82 while still in Congress. As a state legislator, he advocated a bicameral legislature and reform of the penal code and opposed capital punishment. At the Constitutional Convention, where he rarely missed a meeting, he spoke seldom but effectively and played a modest role in shaping the final document.

The next phase of Clymer's career consisted of service in the U.S. House of Representatives in the First Congress (1789-91), followed by appointment as collector of excise taxes on alcoholic beverages in Pennsylvania (1791-94). In 1795-96 he sat on a Presidential commission that negotiated a treaty with the Cherokee and Creek Indians in Georgia. During his retirement, Clymer advanced various community projects, including the Philadelphia Society for Promoting Agriculture and the Pennsylvania Academy of the Fine Arts, and served as the first president of the Philadelphia Bank. At the age of 73, in 1813, he died at Summerseat, an estate a few miles outside Philadelphia at Morrisville that he had purchased and moved to in 1806. His grave is in the Friends Meeting House Cemetery at Trenton, NJ.