We apply a high-resolution hydro-dynamical model to investigate the role of physical factors influencing infection prevalence of Haplosporidium nelsoni, causative agent of MSX disease in the eastern oyster (Crassostrea virginica), in Delaware Bay, USA. Validation studies conducted for the years 2000 and 2010–2011 confirm that the model, based upon the Regional Ocean Modeling System, has significant skill in the recovery of observed water level, temperature, salinity, and velocity. Multi-year simulations are performed for periods representing temporal and spatial variations in H. nelsoni infection prevalence (1974–76, 1979–81, 1984–86, 1990–92, and 2006–09) to assess the degree to which the variations in water properties and transport are temporally and spatially correlated with infection prevalence variations. Results show statistically significant correlations between the observed prevalence of MSX and multiple physical factors including river flow and salinity (themselves highly correlated), as well as the co-occurrence of elevated temperature and salinity values. Observed occurrences of high H. nelsoni infection prevalence at upbay locations correspond to periods of enhanced cross-bay and upbay transport together with hospitable temperature and salinity conditions.