In 1839 he returned to Boston, where he and his friends established (1841) the Church of the Disciples. It brought together a body of men and women active and eager in applying the Christian religion to the social problems of the day, and he would have said that the feature which distinguished it from any other church was that they also were ministers of the highest religious life. Ordination could make no distinction between him and them. Of this church he was the minister from 1841 until 1850 and from 1854 until his death. He was also secretary of the Unitarian Association and, in 1867-1871 professor of natural religion and Christian doctrine at Harvard. From the beginning of his active life he wrote freely for the press.
From 1836 until 1839 he was editor of the Western Messenger, a magazine intended to carry to readers in the Mississippi Valley simple statements of liberal religion, involving what were then the most radical appeals as to national duty, especially the abolition of slavery. The magazine is now of value to collectors because it contains the earliest printed poems of Ralph Waldo Emerson, who was Clarke's personal friend. Most of Clarke's earlier published writings were addressed to the immediate need of establishing a larger theory of religion than that espoused by people who were still trying to be Calvinists, people who maintained what a good American phrase calls "hard-shelled churches."
But it would be wrong to call his work controversial. He was always declaring that the business of the Church is Eirenic and not Polemic. Such books as Orthodoxy: Its Truths and Errors (1866) have been read more largely by members of orthodox churches than by Unitarians. In the great moral questions of his time Clarke was a fearless and practical advocate of the broadest statement of human rights. Without caring much what company he served in, he could always be seen and heard, a leader of unflinching courage, in the front rank of the battle. He published but few verses, but at the bottom he was a poet. He was a diligent and accurate scholar, and among the books by which he is best known is one called Ten Great Religions (2 vols, 1871-1883).
Few Americans have done more than Clarke to give breadth to the published discussion of the subjects of literature, ethics and religious philosophy. Among his later books are Every-Day Religion (1886) and Sermons on the Lord's Prayer (1888). He died at Jamaica Plain, Massachusetts, on June 8, 1888.
His Autobiography, Diary and Correspondence, edited by Edward Everett Hale, was published in Boston in 1891.