The mycobacteriosis epizootic in Chesapeake Bay Atlantic striped bass (Morone saxatilis) is a concern for management because disease-associated mortality can negatively impact the coast-wide stock and its fisheries. As such, it is important to understand environmental drivers of disease dynamics and the consequences of increased disease-associated natural mortality on management reference points. Generalized linear models of fish health survey data collected in Maryland suggest water temperature, hypoxic volume, and fish condition influence disease presence in pre-migratory fish, and hypoxic volume, temperature, condition, age, and sex influence disease severity. Mortality approximately doubled across the range of hypoxic volume and temperature examined. A novel approach to calculating spawning potential ratio was explored to demonstrate the effect of increased natural mortality and compensation assumptions on resulting reference points, yield, and spawning biomass. This work suggests striped bass recovery may require the adoption of more conservative reference points in light of increased natural mortality.