The South Church in Salem, Massachusetts, was formally founded in 1775 by parishioners separating from the Tabernacle Church of Salem after a disagreement with the pastor, Rev. Nathaniel Whitaker. Rev. Whitaker, an initially popular revolutionary and evangelist, was increasingly guiding the Tabernacle toward Presbyterian affiliation. By the end of the year 1773, there was a group within the Tabernacle expressing "their earnest desire that the church be allowed to return and rest upon the stable basis of pure and unmixed Congregationalism." Rev. Whitaker attempted to resolve this conflict by securing the signatures of twenty members to require the decision of a presbytery, which, meeting in September of 1774, suggested that a joint council of both Congregational and Presbyterian advisers decide the matter. The congregation of the Tabernacle church, for unknown reasons, objected to this, and therefore in October of 1774 the aggrieved brethren withdrew their names from enrollment and formed a new society, totaling 14 members. This society was initially known as the Third Church, but changed its name to South Church in 1805 when the Proprietors of the New South Meeting House received incorporation.

The church settled their first pastor, Rev. Daniel Hopkins (1734-1814), in 1775 and ordained him in November of 1778. Rev. Hopkins was a native of Waterbury, Connecticut who had graduated from Yale in 1758. He served as a delegate to the Third Provincial Congress of Massachusetts in 1775, shortly after the outbreak of the American Revolution, and he later served on the Governor's Council from 1776 to 1778. He remained with the church until his death in 1814. However, he suffered from poor health and in April 1805 a second pastor was appointed to assist him, Rev. Brown Emerson (1778-1872), who had graduated from Dartmouth three years earlier. In 1806, Rev. Emerson married Rev. Hopkins' daughter Mary, and went on to serve the church for many years after Rev. Hopkins' death. Like Hopkins, he was also assisted by a younger pastor in his later years, but he remained with the church for a total of nearly 70 years, until his death in 1872 at the age of 94.

For the first 30 years of its existence, the separatist congregation had met in a building on Cambridge Street, but in 1804 construction began on a new meeting house at the corner of Cambridge and Chestnut Streets. This Federal-style building was designed by prominent local architect Samuel McIntire, and included pilasters on the front of the building, a Palladian window, a pediment above the front entrance, and an ornate, multi-stage steeple that rose from the top of the pediment. The first steeple was destroyed in an apparent hurricane on September 11, 1804.

This building was later destroyed by a fire in 1903 and replaced with a stone, Gothic-style church bearing little resemblance to its predecessor. This new building was only used by the South Church for 20 years, after which it re-merged with the Tabernacle Church, in 1924. As of 2019, this organization continues to serve the Salem community as the Tabernacle Congregational Church, UCC.