Etheridge was elected to the State house of representatives in 1845 but served only one term. In 1852, he was elected to the Thirty-third United States Congress as a member of the Whig party. He was re-elected to the Thirty-fourth Congress as a candidate of the American Party. His bid for re-election in 1856 failed, but he was elected as an Opposition Party candidate to the Thirty-sixth Congress in 1859. While in Congress he served as chairman for the Committee on Indian Affairs and as Clerk of the House of Representatives from 1861 to 1863. In 1867, he ran for Governor but lost in a bitterly contested battle to William G. Brownlow.
Etheridge returned to the Tennessee State Legislature in 1869 as a State Senator. In 1878, he was nominated for Governor by the Republican Party but he refused the nomination. He was appointed surveyor of customs in Memphis in his twilight years from 1891 to 1894. He died in Dresden on October 21, 1902. He is interred at Mount Vernon Cemetary outside of Sharon.