Historically, the Lenni Lenape people inhabited the area in the vicinity of Darby Creek. By the 17th century, the Dutch and Swedish had arrived in the area, followed some years later by the English. Numerous mills of various types were eventually build along the creek and several railroads traversed the watershed. In modern times, grants by various organizations have been awarded to improve the creek and its watershed. The Darby Creek Valley Association operates within the watershed. Part of the creek's length is designated as a Coldwater Fishery and a Migratory Fishery, part is a Trout Stocked Fishery and a Migratory Fishery. Various species of fish, including redbreast sunfish, eels, and trout, inhabit it. Several areas in the vicinity of the creek are listed on the Delaware County Natural Areas Inventory. These include the Darby Creek Mouth Mudflat, the John Heinz National Wildlife Refuge, and the Ithan-Darby Creek Wetlands. A reach of the creek is navigable by canoe.