In 1855 illness precluded Cox from assuming a diplomatic appointment as secretary to the American legation in Lima, Peru. The next year, however, he won election as a Democrat to the House of Representatives, where he would spend most of his professional career. During the political strife of the late 1850s, Cox advocated compromise on the slavery issue. Once the Civil War began, he supported the war effort to restore the Union, but opposed emancipation and violations of civil liberties. Although he was personally opposed to racial equality and voted against the Thirteenth Amendment, he also believed that the Democratic party needed to shed its pro-slavery image; therefore, he convinced enough of his Democratic colleagues to abstain so that the amendment abolishing slavery was able to pass the House.

Having lost his reelection bid in the 1864 election because of gerrymandering, Cox moved in the spring of 1865 to New York City to practice law. Backed by Tammany Hall, he won another seat in Congress in 1868. Known for his wit and eloquence, Cox opposed Republican policies of Radical Reconstruction and high tariffs. His two pet causes were the Life Saving Service and the Post Office for which he strove to improve the service and working conditions of both. In 1872 gerrymandering again resulted in a reelection loss, but he won a special election the next year following the death of James Brooks. When the Democratic party secured a House majority in the 1874 elections, Cox expected to win the speakership. Michael Kerr of Indiana was selected instead, but Cox served as speaker pro tempore during Kerr's long illness. Despite that position and committee chairmanships, Cox was less influential and effective than he had been in the past as a leader of the minority.