He served as the president of the Kentucky Central Railroad before returning to Congress. Pendleton won election to the U.S. Senate in 1879 and served a single term, becoming Chairman of the Senate Democratic Conference. After the assassination of President James A. Garfield, he wrote and helped pass the Pendleton Civil Service Reform Act of 1883. The act required many civil service hires to be based on merit rather than political connections. Passage of the act lost him support in Ohio and he was not nominated for a second term in the Senate. President Grover Cleveland appointed him as the ambassador to the German Empire. He served in that position until 1889, dying later that same year.