The museum's core collection was started in childhood by the naturalist, philanthropist and high-profile convicted murderer[2][3][4] John E. ("Golden Eagle") du Pont.

During and after graduate school, du Pont took part in several scientific expeditions to the South Pacific and the Philippines, and is credited with the discovery of two dozen subspecies of birds.

At his request, his uncle Henry Francis du Pont provided land across from the Winterthur estate in the Brandywine Valley of Delaware for the museum.

[6] The museum originally was based on du Pont's collection of 1,000,000 sea shells and 100,000 bird eggs.

In early studies, these were used by scientists to measure pesticide contamination of wild species.