Despite nearly a century of exploitation and scientific study, predicting growth and mortality rates of the eastern oyster (Crassostrea virginica) as a means to inform local harvest and management activities remains difficult. Ensuring that models reflect local population responses to varying salinity and temperature combinations requires locally appropriate models. Using long-term (1988 to 2015) monitoring data from Louisiana's public oyster reefs, we develop regionally specific models of temperature- and salinity-driven mortality (sack oysters only) and growth for spat (<25 mm), seed (25–75 mm), and sack (>75 mm) oyster size classes. The results demonstrate that the optimal combination of temperature and salinity where Louisiana oysters experience reduced mortality and fast growth rates is skewed toward lower salinities and higher water temperatures than previous models have suggested. Outside of that optimal range, oysters are commonly exposed to combinations of temperature and salinity that are correlated with high mortality and reduced growth. How these combinations affect growth, and to a lesser degree mortality, appears to be size class dependent. Given current climate predictions for the region and ongoing large-scale restoration activities in coastal Louisiana, the growth and mortality models are a critical step toward ensuring sustainable oyster reefs for long-term harvest and continued delivery of the ecological services in a changing environment.