His father had been a member of the Ohio Senate from 1825 until 1827. In 1854, he ran unsuccessfully for the Thirty-fourth United States Congress. Three years later, he was elected as a Democrat to the Thirty-fifth Congress and would be re-elected to the three following Congresses (March 4, 1857 – March 3, 1865). During his time in the House of Representatives, he was one of the managers appointed by the House of Representatives in 1862 to conduct the impeachment proceedings against West H. Humphreys, a US judge for several districts of Tennessee. He was a leader of the peace faction of his party, with close ties to the Copperheads. He voted against the Thirteenth Amendment, which outlawed slavery and involuntary servitude. Pendleton ran as an antiwar Democrat in the 1864 presidential elections for Vice President, together with George McClellan. Their opponents were Lincoln (President) and Andrew Johnson (nominee for Vice President). At 39, Pendleton was one of the youngest candidates for national office in US history. McClellan and Pendleton lost, receiving about 45% of the vote. In the same election, Pendleton also lost re-election to the Thirty-ninth Congress. Out of office for the first time in a decade, Pendleton ran for his old House seat in 1866 but lost. In 1868, he sought the Democratic Party's presidential nomination. He led for the first 15 ballots and was nearly the nominee, but his support disappeared and he lost to Horatio Seymour, primarily for his support of the "Ohio idea." The following year, he was the Democratic nominee for Governor of Ohio and again lost, this time to Rutherford B. Hayes. Pendleton stepped away from politics, and in 1869, he became president of the Kentucky Central Railroad. In 1879, he made his comeback when he was elected as a Democrat to the United States Senate. During his only term, from 1881 to 1885, he served concurrently as the Chairman of the Democratic Conference. Following the 1881 assassination of James A. Garfield, he passed his most notable legislation, known as the Pendleton Act of 1883, requiring civil service exams for government positions. The Act helped put an end to the system of patronage in widespread use at the time, but it cost Pendleton politically, as many members of his own party preferred the spoils system. He was thus not renominated to the Senate. Instead, President Grover Cleveland appointed him Envoy Extraordinary and Minister Plenipotentiary to Germany the year that he left office, which he served until April 1889.