A member of the New Light Church, a Separatist sect, Backus began preaching in 1746, traveling throughout Connecticut and Massachusetts. He was ordained in 1748 and established a congregation in the precinct of Titicut, Mass. Controversy surrounding his opposition to infant baptism, however, forced him to leave in 1756. Later that year he organized a Baptist church, where he served as pastor until his death. He became a leading spokesman for the Baptist church and wrote A History of New England, with Particular Reference to the Denomination of Christians Called Baptists (1777–96). Backus fought for religious freedom and served on several committees that examined discrimination against Baptists.

Although Backus did not attend a college or religious seminary, he was awarded an honorary degree by Rhode Island College (now Brown University) in 1797.