It rises in northern Sussex County, approximately 3 miles southwest of Milford, and flows generally east-northeastwardly, defining the Sussex and Kent boundary; it passes through the center of Milford on its course to the Delaware Bay.
Slaughter Beach was home to the last wooden frame lighthouse in Delaware, the Mispillion Lighthouse. The lighthouse, which overlooked the Mispillion River and Cedar Creek, was established in 1831 with a 65-foot tower.
Slaughter Beach is also home to the Milford Neck Wildlife Area. Tourists are attracted to this area for birding, as many birds stop over to eat the eggs of horseshoe crabs as they lay their eggs on the beaches. Along with Broadkill, Fowler, Kitts Hummock, Pickering, and Primehook beaches, this area is officially designated as a sanctuary for horseshoe crabs, the state marine animal of Delaware and a "signature species" of the Delaware Bay Estuary.
Silver Lake is a privately owned brackish water pond in Milford, Delaware. It is located by the headwaters of the Mispillion River. Haven Lake is adjacent to Silver Lake. U.S. Route 113 travels between the two lakes, crossing the Mispillion River. On the river, there was a milldam established in the late 18th century, which formed Silver Lake. The mill was replaced in the 19th century