Prior to English colonization, the are today known as Charlestown, Boston, Massachusetts, was inhabited by the indigenous Massachusett. Charlestown was called Mishawum by the Massachusett. The first English colonizers were Thomas and Jane Walford who arrived in Mishawum in 1624. Charlestown proper was founded in 1628 and formally settled on July 4, 1629. A church was founded in Charlestown in 1630, but when John Winthrop accepted William Blaxton's invitation to settle on the Shawmut peninsula, the majority of that early church's membership withdrew. The 35 original members of the church who still resided in Charlestown sought dismissal from the church and recovenanted as the First Church of Charlestown on November 2, 1632. The first meeting house was made from Governor Winthrop's “Great House” and a second meeting house was built in 1636. John Harvard was the church's third minister; he died in 1638. Harvard College was renamed in honor of John Harvard after he had bequeathed his entire library and half of his monetary estate to the college in his will.

The third meetinghouse was constructed in 1715. That building was destroyed during the Battle of Bunker Hill, during the American Revolution, when British troops almost completely destroyed the town. The town did not truly begin to rebuild until after the American Revolutionary War ended in 1783; the fourth meeting house was constructed in 1783. This building was expanded in 1804. The fifth meeting house was constructed in 1834 and the sixth was constructed in 1853. In 1834, a second Congregational Church, known as the Winthrop Congregational Church, was gathered. This church merged with the First Church in 1913 and the Winthrop Church building became the First Church's seventh church building.

In 1957, the church's interior was destroyed by a fire. The church suffered financial hardships following the fire and the building could only be restored after many years. During the racial protests and violence which enveloped Boston between 1974 and 1976, the First Church became a safe haven for African American students. In 2014, the church began a revitalization process with Celebration Church, a Brazillian congregation; the result of this partnership was a refurbished church building in 2016. In 2015, with the installation of Erik Maloy, the church became a member of the Southern Baptist Convention alongside its continued membership with the United Church of Christ. In 2022, the First Church merged with Christ Church Charlestown who inherited the church building and now holds worship there.