Chase received part of his education from his uncle Philander Chase, the first Episcopal bishop of Ohio and later of Illinois, and his legal training (1827–30) from William Wirt, U.S. attorney general. From 1830 he practiced law in Cincinnati, Ohio, where he became widely known for his courtroom work on behalf of runaway slaves and white persons who had aided them. Originally a Whig, he changed his politics according to fluctuations in the antislavery movement. After leading the Liberty Party in Ohio (from 1841), he helped to found the Free-Soil Party (1848) and the Republican Party (1854). Between terms in the U.S. Senate (1849–55, 1860–61), he was the first Republican governor of Ohio (1855–59). He sought the Republican presidential nomination openly in 1856 and 1860, and surreptitiously in 1864 while serving in Lincoln's Cabinet; in 1868, during his chief justiceship, he sought the Democratic nomination as an opponent of the Radical Republicans' program of reconstructing the defeated Southern states, and in 1872 he was once more an unsuccessful candidate.

At the 1860 Republican convention in Chicago, Chase permitted the delegates pledged to him to cast decisive votes for Lincoln (Lincoln, Abraham) on the third ballot. As a reward Lincoln appointed him secretary of the Treasury, in which position for the next three years he was responsible for financing the Union war efforts. He held the Treasury post until June 1864, and in December of that year he was appointed chief justice to succeed Roger Brooke Taney, who had died in October.