Monitoring wild fish health and associated exposure effects in regions where agriculture and development have impacted rivers and streams has become a valuable research tool. Smallmouth bass (Micropterus dolomieu) are a sensitive, indicator species that exhibit symptoms of immunosupression and endocrine disruption in response to water quality changes and contaminant exposure. In the Susquehanna River drainage, smallmouth bass have been used in biomonitoring assessments to help understand changes in the population due to poor young-of-the-year recruitment and health effects. To help determine effects of agriculture and development on smallmouth bass health, two sites (a developed/agriculture site and a forested site) were selected where bass and water chemistry were sampled from 2015-2019. Bass were sampled for histopathology to assess parasite and macrophage aggregate density in the liver and spleen, condition factor (Ktl), hepatic gene transcripts (immune function, oxidative stress, cell proliferation, stress, and contaminant, thyroid, and insulin/pancreas metabolism), hepatosomatic index (HSI), and a health assessment index (HAI). Land use at the developed/agricultural site included greater pesticide application rates and % high phytoestrogen crop cover and there were more detections and higher concentrations of pesticides, wastewater-associated contaminants, hormones, phytoestrogens, and mycotoxins than at the forested site. Additionally at this site, oxidative stress, lipid metabolism, and thyroid-related hepatic gene transcripts were associated with contaminants/land use applications; whereas at the forested site there were far fewer associations. At both sites, there were multiple associations of contaminants/land use applications with biological variables (HSI, Ktl, and liver and spleen macrophage aggregate density), which may indicate that changes at the molecular level may be a better indicator of exposure effects unique to each site. This work will help to understand the importance of timing for land management practices, how contaminants change temporally, and that agricultural practices affect hepatic gene transcripts associated with immune function and disease resistance and may negatively affect the health of smallmouth bass.