Evidence of disease and mortalities of young of the year (age‐0) Smallmouth Bass Micropterus dolomieu has occurred during the late spring and summer in many parts of the Susquehanna River watershed since 2005. To better understand contributing factors, fish collected from multiple areas throughout the watershed as well as out‐of‐basin reference populations (Allegheny and Delaware River basins; experimental ponds, Kearneysville, West Virginia) were examined grossly and histologically for abnormalities. Tissue contaminant concentrations were determined from whole‐body homogenates, and water contaminant concentrations were estimated using time‐integrated passive samplers at selected sites. Observed or isolated pathogens included bacteria, predominantly motile Aeromonas spp. and Flavobacterium columnare ; largemouth bass virus, and parasites, including trematode metacercariae, cestodes, and the myxozoan Myxobolus inornatus . Although these pathogens were found in age‐0 Smallmouth Bass from multiple sites, no one pathogen was consistently associated with mortality. Chemicals detected in tissue included polychlorinated biphenyl (PCB) congeners, organochlorine, and current‐use pesticides. Pyraclostrobin, PCB congeners 170 and 187, cis‐chlordane and trans‐nonachlor were detected in all Susquehanna watershed samples but rarely in samples from the reference site. The findings support the idea that there is no single cause for disease of age‐0 Smallmouth Bass; rather the cumulative effects of co‐infections and potential immunomodulation by environmental stressors during a sensitive developmental life stage may lead to mortality. Identifying the most important risk factors will be necessary for more in‐depth analyses of individual stressors and better management of the habitat and fish populations.