The Clinch River, in eastern United States, supports a diverse freshwater fauna including endangered mussels. Although mussel populations are stable in the Clinch's northeastern Tennessee segment, long-term declines have been documented upstream in Virginia. We analyzed water and sediment quality data collected by government agencies from the 1960s through 2013 in an effort to inform current management. The river was divided into sections considering data availability and major tributaries. We tested for spatial differences among river sections and for temporal trends, and compared measured values to potentially protective levels if available. Ammonia concentrations approaching and exceeding protective levels were recorded, most often during the 1970s and 1980s in upstream sections. Sediment metals occurred at levels potentially causing biological effects, mainly during the 1980s and 1990s. In the 2000s, water-column metals have been well below protective levels for general aquatic life. Dissolved solids (DS) increased in most river sections over the study period but mussel-specific protective levels are not known. Analysis of water pH, total N, and total P did not generate conservation concern. Enhanced monitoring for sediment metals, water-column metals, and ionic composition of DS; closer alignment of agency water monitoring practices in the two states; and research to determine biological effects of DS at current and anticipated levels can aid future conservation management.