During the eighteenth century, many German Reformed adherents emigrated to Pennsylvania and neighboring colonies from Germany and Switzerland, often to escape wars in Europe. On September 21, 1727, the Reverend George Michael Weiss and 400 members of the German Reformed Church arrived in Philadelphia from the Palatinate region of western Germany. They settled in a neighborhood east of Broad Street and north of Market Street. Weiss, the first ordained German Reformed minister in North America, began holding services soon after his arrival. The congregation he organized in 1727 became Philadelphia's Old First Reformed Church.

The Old First Reformed Church has gone through several changes in denominational affiliation. Originally, all German Reformed congregations in North America were supervised by the Dutch Reformed Church in Holland. The Synod of the German Reformed Church in the United States of America, a body independent of the European church, was formed in 1793. In 1863, it changed its name to the Reformed Church in the United States. Largely reflecting this denominational evolution, the name of the Old First Reformed Church has changed repeatedly. Originally it was known as the German Reformed Congregation or German Reformed Church, less commonly as High German Reformed Church, High German Evangelical Reformed Church, or Calvinist Congregation. Later the congregation took the name First Reformed Church. Today, it is the United Church of Christ (UCC).

The congregation of the First Reformed Church maintained a cemetery on the northeast corner of what is today Franklin Square (originally called Northeast Public Square), bounded by Eighth and Seventh streets and Race and Vine streets, from 1741 until 1835, when the city reclaimed the land for use as a park. At that time, some of the bodies were moved to a graveyard the church had purchased in 1801 on the west side of 17th Street between Arch and Cherry Streets, while the gravestones for others were laid flat and covered over. The congregation later replaced the Cherry Street graveyard and the graves were moved again, to Lot 1, West Laurel Hill Cemetery, which it purchased with the help of money awarded by the City of Philadelphia.

Note that a splitter congregation, calling themselves the Second Reformed Association, left the church in 1806. In 1810 the name was changed to Evangelical Reformed Congregation and in 1813 to the First Reformed Protestant Dutch Church. Its defunct burial ground nearby should not be confused with this congregation's.