At the time of European settlement of the Low Country, Alexander Mackey, for whom adjacent Mackey Island is named, received two proprietary grants by edict of the English throne, including the land that became Pinckney Island. Shortly thereafter, it came into the possession of Charles Pinckney, who in turn deeded it to his son in Charles Cotesworth Pinckney (1746-1825) was a native South Carolinian and one of her foremost representatives in the founding of the United States. Though educated in England, Pinckney was an ardent patriot and rose to the rank of general in the Continental Army. He participated in the 1779 Siege of Savannah, which featured other notable warriors such as South Carolina's Francis Marion, known as the Swamp Fox, and Count Casimir Pulaski, a Polish nobleman who fought bravely and fell at Savannah. Though the Siege of Savannah was initially unsuccessful, Pinckney survived, the colonies were freed, and Pinckney went on to participate in the First and Second Provincial Congresses. He was one of the signers of the United States Constitution. Later he served in the South Carolina Assembly, and was a delegate to the 1790 South Carolina Constitutional Conven-tion. At the time of his ownership the island was a plantation, Pinckney was able to spend only a little time overseeing its workings; his proprietorship directly coincided with the Revolution and duty called him away.

In the early years of the twentieth century, the Pinckney Island became a hunting preserve, and game stock was introduced to the island. By 1975, however, the island was again transformed when the U.S. Fish and Wildlife Service acquired the property. Today it is maintained as a refuge, with the Service slowly bringing the land back to its natural marshland state. The island contains nearly 4,000 acres of varied terrain. Twenty percent of the land is forested; the rest is a combination of grass and brushland, freshwater ponds, and salt marsh and tidal creeks. The Wildlife Service has documented over 250 species of birds on the island, including Wading Birds, varieties of these birds include the Egret, Heron, and Ibis. White-tailed deer also may be found on the island, and the Service allows controlled hunting in season.

Pinckney Island features over fourteen miles of trails and roads, some dating from the plantation era, and visitors may hike these or ride their bicycles along them. The Wildlife Service uses forestry practices to foster the ecological diversity of the land. These include hardwood planting and selective cutting, pinewood thinning, and controlled burning. Freshwater fishing is strictly prohibited, but guests are invited to fish, shrimp, and crab by boat in the numerous creeks along the refuge, which also includes the adjacent Big Harry Island, Little Harry Island, Corn Island, and Buzzard Island.