The first Presbyterian services in this area were conducted by Rev. John Wilson in 1706. Then pastor of New Castle Presbyterian Church, Rev. Wilson came every other Sunday to minister to the many residents of this area who had immigrated from Scotland and Ireland. In 1708, a modest log structure was erected on land owned by John Steel. The first installed pastor was Rev. George Gillespie, a native of Scotland, who arrived in 1713 and served until his death in 1760. During his tenure the log building was replaced by a brick structure which served the congregation until it was destroyed by fire in 1858. Within one year, the present church was built, and while alterations have been made, the basic structure remains intact.
A number of critical issues have impacted the church over the years. Many members were ardent patriots and active participants in the struggle for American Independence. In the 19th century the question of slavery proved divisive, with partisans within the church on both sides of the issue. During the 1930s a dispute concerning theological matters resulted in an attempt to separate from the established church. For a time the church was closed, but the efforts of a few trustees and elders resulted in a court action that barred the move, and the building was reopened. Since that time the congregation has grown and prospered, adding new members, and expanding its ministry. In 1983, Head of Christiana Presbyterian Church was listed in the National Register of Historic Places.
The church and its adjacent cemetery are very well maintained.