After studying at the University of Cincinnati and Heidelberg University, Pendleton practiced law in his home town of Cincinnati, Ohio. He was the son of Congressman Nathanael G. Pendleton and the son-in-law of poet Francis Scott Key. After serving in the Ohio Senate, Pendleton won election to the United States House of Representatives. During the Civil War, he emerged as a leader of the Copperheads, a group of Democrats who favored peace with the Confederacy. After the war, he opposed the Thirteenth Amendment and the Civil Rights Act of 1866.