The eastern oyster, Crassostrea virginica, provides critical ecosystem services and supports valuable fishery and aquaculture industries in northern Gulf of Mexico (nGoM) subtropical estuaries where it is grown subtidally. Its upper critical thermal limit is not well defined, especially when combined with extreme salinities. The cumulative mortalities of the progenies of wild C. virginica from four nGoM estuaries differing in mean annual salinity, acclimated to low (4.0), moderate (20.0), and high (36.0) salinities at 28.9 °C (84 °F) and exposed to increasing target temperatures of 33.3 °C (92 °F), 35.6 °C (96 °F) or 37.8 °C (100 °F), were measured over a three-week period. Oysters of all stocks were the most sensitive to increasing temperatures at low salinity, dying quicker (i.e., lower median lethal time, LT₅₀) than at the moderate and high salinities and resulting in high cumulative mortalities at all target temperatures. Oysters of all stocks at moderate salinity died the slowest with high cumulative mortalities only at the two highest temperatures. The F1 oysters from the more southern and hypersaline Upper Laguna Madre estuary were generally more tolerant to prolonged higher temperatures (higher LT₅₀) than stocks originating from lower salinity estuaries, most notably at the highest salinity. Using the measured temperatures oysters were exposed to, 3-day median lethal Celsius degrees (LD₅₀) were estimated for each stock at each salinity. The lowest 3-day LD₅₀ (35.1–36.0 °C) for all stocks was calculated at a salinity of 4.0, while the highest 3-day LD₅₀ (40.1–44.0 °C) was calculated at a salinity of 20.0.