After a brief attendance at Miami University in Oxford, Ohio, Morton set up a law practice in Centerville, Ind., in 1845 and involved himself in Democratic politics. Breaking with the party over the Kansas–Nebraska Act of 1854, he participated in the formation of the Republican Party and in 1856 ran unsuccessfully for governor of Indiana. Elected lieutenant governor in 1860, he became governor the next year when Governor Henry S. Lane resigned to enter the U.S. Senate.

As a war governor, Morton achieved fame through his vigorous handling of political forces bent on disunion. Faced with a hostile legislature in 1863, he governed for two years virtually by fiat, raising the necessary funds through private appeals. After the war Morton was elected to the U.S. Senate (1865), where at first he supported the moderate policies of President Andrew Johnson (Johnson, Andrew). He soon altered his views, however, and emerged as a leader of the Radical Republicans (Radical Republican), voting for President Johnson's impeachment and urging immediate black suffrage. A prominent, though unsuccessful, candidate for the Republican nomination for the presidency in 1876, he was hampered by his physical condition (a stroke suffered in 1865 left him paralyzed below the waist) as well as by his partisanship.