In 1785, Weakley moved to the part of North Carolina that later became Tennessee and engaged in agricultural pursuits. He was a member of the North Carolina convention that ratified the Constitution of the United States in 1789. In 1791, he was the Brigade Inspector of the militia of Mero District, in what was then the Southwest Territory. In 1796 he was elected to the first Tennessee House of Representatives. In 1798, he was a Colonel of the 2nd Regiment of the Davidson County Militia. He served as Senator in the Tennessee Senate in 1799, 1803, 1807 and 1819.