When Scots Irish filtered into the Cumberland Valley in the 1730s, they settled along creeks. One of the first churches was organized at Meeting House Springs. A log meeting house was built on the southern bank of the Conodoguinet about two miles northwest of Carlisle in 1737. The Rev. Samuel Thomson became the pastor in 1739. By 1759, the congregation left Meeting House Springs and divided into two congregations that moved to Carlisle, the established county seat since 1751.
Construction is believed to have been completed within the next year or two.
The church was at the center of American history in its early years. A convention of colonists met at the church in 1774 and passed a resolution for independence. Among those attending were John Montgomery, James Wilson, Col. John Armstrong, William Irvine, William Thompson, Robert Magaw and Ephraim Blaine. In 1794 President George Washington came to Carlisle to review troops heading to western Pennsylvania to quell the Whiskey Rebellion. While staying in Carlisle he attended worship services at the church.