He served as a United States Senator from Tennessee twice, once from 1811 to 1814, having been elected to fill the seat of Jenkin Whiteside, and again from 1815 to 1818. His first service was from October 8, 1811 to February 11, 1814, when he resigned to accept appointment as the United States Secretary of the Treasury. He returned to the Senate on October 10, 1815. He served as the first chairman of the Senate Finance Committee and its predecessor from December 4, 1815, until his resignation from the Senate on April 20, 1818; on this occasion to accept appointment as United States Ambassador to Russia, a position he held from 1818-1821. Campbell served as a member of the French Spoliation Claims Commission in 1831.