Muddy Run is a tributary of Spruce Run in Union County, Pennsylvania, in the United States. It is approximately 4.8 miles (7.7 km) long and flows through West Buffalo Township and Buffalo Township. The watershed of the stream has an area of 4.57 square miles (11.8 km2). Part of the stream is designated as an impaired waterbody due to sedimentation and siltation from grazing-related agriculture.