Freshwater mussels are among the most-imperiled organisms worldwide, although they provide a variety of important functions in the streams and rivers they inhabit. Among Atlantic-slope rivers, the Delaware River is known for its freshwater mussel diversity and biomass; however, limited data are available on the freshwater mussel fauna in the lower, non-tidal portion of the river. This section of the Delaware River has experienced decades of water-quality degradation from both industrial and municipal sources, primarily as a function of one of its major tributaries, the Lehigh River. We completed semi-quantitative snorkel surveys in 53.5 of the 121 km of the river to document mussel community composition and the continued impacts from pollution (particularly inputs from the Lehigh River) on mussel fauna. We detected changes in mussel catch per unit effort (CPUE) below the confluence of the Lehigh River, with significant declines in the dominant species Elliptio complanata (Eastern Elliptio) as we moved downstream from its confluence—CPUE dropped from 179 to 21 mussels/h. Patterns in mussel distribution around the Lehigh confluence matched chemical signatures of Lehigh water input. Specifically, Eastern Elliptio CPUE declined more quickly moving downstream on the Pennsylvania bank, where Lehigh River water input was more concentrated compared to the New Jersey bank. A definitive causal link remains to be established between the Lehigh River and the dramatic shifts in mussel community composition, warranting continued investigation as it relates to mussel conservation and restoration in the basin.