The first quarantine station in Philadelphia was erected in 1743 on Province Island, just southwest of where the Schuylkill and Delaware Rivers meet on present-day Penrose Ferry Road. A building was erected to quarantine sick travelers arriving at the port of Philadelphia, and this became known as the "Pest House," and later the "Old Lazaretto." A burial ground was likely to have been established contemporaneously for those travelers who died at the station.

Following the creation of the Board of Health in 1799, the quarantine station was transferred to a newly built structure located about six miles west in Tinicum Township in 1801. That same year, an act of legislature authorized the sale of the old Lazaretto grounds on what had been renamed "State Island," the proceeds going towards the construction of the new building. In 1808 the Board of Health conveyed the old grounds to the United States Government for $5,000.

Managed by the Department of War throughout the 19th century as part of a larger government military reservation around Fort Mifflin, around the year 1851, the quartermaster general's office transferred the Old Lazaretto lot to the fort for their use as a vegetable garden and burial ground — likely near one of the "witness trees" marking the property boundary.

A farmer whose land adjoined the government reservation recalled that when he was a boy, five soldiers had been buried here, their bodies being brought from graves at the old Fort Mifflin post cemetery. Nancy Sharp, wife of Fort Mifflin Lighthouse keeper Henry H. Sharp, said that she had heard that a family named Brandt had made several interments in the place, but only soldiers' graves were located in the late 19th century. The know burials here dated to the 1840s and 1850s.

During the Civil War, Fort Mifflin was again called to action and housed Union and Confederate prisoners. Government rolls from the time record only one official burial at Fort Mifflin from that time — Private William Fisher, of Company F, 56th Regiment, Pennsylvania Volunteer Infantry, who died on August 28th, 1864 — but he was actually interred at Mount Moriah Cemetery.

By 1896, the burial ground had become an overgrown in a thick "jungle" of vines and poison ivy on a small island in the marshes around a walnut tree; neighbors recalled little about it, and the War Department at the time could find no records of the burial ground or had it marked on their surveys.

Reporting forced the government to act. On October 1, 1896, those remains that could be identified were removed to Section A of Philadelphia National Cemetery. However, a number of bodies remained in the old plot, which was subsequently looted in search of artifacts in January, 1897.

During the First World War, the site of the Old Lazaretto was built over for the Naval Ammunition Depot, Fort Mifflin. Today the area is the U.S. Army Corps of Engineers Fort Mifflin Disposal Area. No trace of the burial ground remains, having been covered by dredging spoils.