After graduating from Harvard College and Harvard Divinity School, Clarke served in Louisville, Kentucky, where he established the Western Messenger, a periodical of the Transcendentalist movement.

Moving to Boston, he founded the Church of the Disciples in 1841 and was one of the few ministers to exchange pulpits with Theodore Parker. After a serious health crisis in 1849, he resumed his Boston ministry for 34 more years.

Clarke proclaimed five points of Unitarian faith:

       1. The Fatherhood of God
       2. The Brotherhood of Man
       3. The Leadership of Jesus
       4. Salvation by Character and
       5. The Progress of Mankind, onward and upward forever.

In contrast to the Transcendentalists and the Free Religious Association, Clarke united with Frederic Henry Hedge and Henry W. Bellows in a Broad Church movement committed to unified Unitarian church organization for action.

One of his books, Ten Great Religions, is an early comparative study of world religions.