The St. John's congregation dates its origins to the 1742 arrival of Dr. Henry Melchior Muhlenberg, the father of the Lutheran Church in America. He stopped for two days in Charleston on his way to visit the Salzburger colony at Ebenezer, Georgia. He returned a month later and spent three weeks waiting for a ship to Philadelphia during which time he held services, taught catechism to the children of the German residents, and held services with communion on Sundays.

Rev. Dr. John Bachman (1790-1874) brought a golden era to St. John's in the nineteenth century, but it ended abruptly when Charleston and St. John's were devastated by the War Between the States.

A brief period of racial enlightenment largely disappeared after the Civil War, but had made an important mark in American Christian history while it lasted. Three of the nation's most important early African-American leaders came from St. John's, and the first group of Lutherans to send an American missionary to Africa also took place within the congregation.