After moving to Indianapolis, Harrison established himself as a prominent local attorney, Presbyterian church leader, and politician in Indiana. During the American Civil War, he served in the Union Army as a colonel, and was confirmed by the U.S. Senate as a brevet brigadier general of volunteers in 1865. Harrison unsuccessfully ran for governor of Indiana in 1876. The Indiana General Assembly elected Harrison to a six-year term in the U.S. Senate, where he served from 1881 to 1887.