Fish diseases in freshwater ecosystems pose significant ecological and socioeconomic challenges, yet monitoring them in wild populations is complex due to interactions between pathogens, hosts, and environmental conditions. We examine the prevalence and watershed-scale landscape drivers of external deformity, erosion, lesion, tumor, and parasite (DELT) anomalies in 57 riverine fish species using a large dataset (577,266 individuals collected 2008–2019) from the Chesapeake Bay watershed that originated from state and federal agencies. Overall, DELT prevalence was low (1.4%), but was higher in larger, longer-lived species, including Channel Catfish (Ictalurus punctatus) (18.9%), Rock Bass (Ambloplites rupestris) (7.6%), Smallmouth Bass (Micropterus dolomieu) (7.3%), Brown Bullhead (Ameiurus nebulosus) (5.6%), and Yellow Bullhead (Ameiurus natalis) (5.1%), signifying their potential as regional environmental health indicators. Spatial analysis indicated warmer temperatures increased the estimated probability of DELT occurrence, whereas higher precipitation often mitigated the probability of DELT occurrence. Conservation strategies (e.g., best management practices) had mixed effectiveness in reducing DELT occurrence probability across agricultural and urban landscapes. Across the landscape, various drivers, including harvested forest, impervious land, and pesticide use, influenced DELT occurrence probability differently across species. However, uncertainty remains partly due to low prevalence and variability in sampling methods across agencies. Despite low overall prevalence, DELT occurrence is a rapid fish health indicator. Future research could emphasize species-specific responses and longitudinal studies that incorporate life stages and health indicators. Understanding these intricate, multi-scale interactions is vital for effective monitoring, conservation, and adaptive management of freshwater ecosystems.