Lancaster Cemetery was the first of Lancaster's "rural cemeteries." In 1846 the vestry of the German Reformed Church acquired a ten acre property along the New Holland Turnpike north of the city, and the following year received a charter of incorporation from the state legislature which guaranteed perpetual occupancy of the dead. The cemetery was designed by the Reverend Nathaniel A. Keyes, who apparently laid out the relatively flat grounds using a compass and a ruler.

Among the notable individuals interred in Lancaster Cemetery are Civil War General John Fulton Reynolds, who died on the first day of the battle of Gettysburg, July 1, 1863, and modern artist Charles Demuth. Lancaster Cemetery has been designated a local historic landmark by the Historic Preservation Trust of Lancaster County.