In Newport, Rhode Island, William's father died when he was thirteen. His mother's father, William Ellery—who had signed the Declaration of Independence—then helped to care for him. When William graduated as class orator, tiny Harvard College was limited to just a few buildings.

A traumatic experience followed when Channing became the tutor of children in Richmond, Virginia. Inner torment arose from his wrestling with traditional religious demands which so disturbed his body-mind as to affect his health then and thereafter. Having decided to become a minister, he joined the First Church in Cambridge, then served by Dr. Abiel Holmes. When he was twenty-three, in 1803, he was ordained by the Federal Street Church in Boston—now the Arlington Street Church—which he served until his death.

He proclaimed his growing liberalism when he delivered his address on Unitarian Christianity at the ordination of Jared Sparks in Baltimore in 1819. At what has been called the Pentecost of Unitarianism, he articulated a manifesto of the movement of liberal Christians. His rigorous repudiation of the Calvinisitic doctrines of human depravity, predestination, and eternal damnation united with his invigorating affirmation of human freedom and human dignity.

In 1820, he invited colleagues to his parsonage to form an organization uniting liberal clergy. They formed the Berry Street Conference, which led in 1825 to the adoption of a constitution for the American Unitarian Association.

During his lifetime he contributed in notable ways to philosophy, literature, education, and social reform.