Eastern oysters Crassostrea virginica support a critical commercial industry and provide many ecosystem services to coastal estuaries yet are currently threatened by changing estuarine conditions. A changing climate and the effects of river and coastal management are altering freshwater inflows into productive oyster areas, causing more frequent and extreme salinity exposure. Although eastern oysters are tolerant to a wide range of salinity means and variations, more frequent and extreme exposure to low salinity (<5‰) impacts oyster populations and aquaculture operations. This study assessed four Louisiana eastern oyster stocks to explore population-specific responses to low-salinity exposure. Hatchery-produced progeny (10–25 mm) were deployed in baskets kept off-bottom on longline systems in a low-salinity (mean ± 1 standard error of the mean daily salinity = 8.7 ± 0.2‰; range = 1.2–19.0‰) and a moderate-salinity (16.8 ± 0.3‰; 4.8–30.0‰) environment for 1 year, beginning in December 2019, with growth and mortality determined monthly. Significant differences in cumulative mortality between stocks at the end of the study were found at the low-salinity site, with the greatest increase in cumulative mortality occurring mid-July to mid-August. Mortality differences between stocks suggest that some eastern oyster populations (i.e., stocks) may be better suited to low salinity or low-salinity events than others. This difference may be attributed to similarity between site of origin and grow-out site conditions and/or to greater salinity variability and therefore higher phenotypic plasticity in some eastern oyster populations compared with others. The identification of oyster stocks able to survive under extreme low-salinity conditions may facilitate the development of “low-salinity-tolerant” broodstock to support aquaculture in areas experiencing and predicted to experience low-salinity events.