Born in Petersburg, Indiana, and raised in Evansville, Indiana, he was first a lawyer and then served as general for the Union in the American Civil War. Following the war he worked as a journalist, editing the Evansville Daily Journal from 1865 to 1869. Thereafter he was the U.S. Minister to Mexico (1873-1880), to Russia (1880-1881) and to Spain (1883-1885). In the Benjamin Harrison Administration he served as a State Department "trouble shooter" before replacing James G. Blaine who had succumbed to what became a fatal attack of Bright's Disease. He served as U.S. Secretary of State under President Benjamin Harrison in 1892 and 1893. He also helped the Qing Dynasty in drafting the Treaty of Shimonoseki of 1895 as a legal consultant and commissioner.
His grandchildren included John Foster Dulles, who also became a U.S. Secretary of State, Allen Welsh Dulles, a Director of Central Intelligence, Eleanor Lansing Dulles, economist and diplomat. He is also the great-grandfather of the noted Catholic theologian, Avery Cardinal Dulles.