Rising seawater temperature induces heat stress in marine organisms, particularly in the marine invertebrates, due to their poikilothermic nature. In this study, we observed changes in tissue morphology, extrapallial fluid (EPF, a body fluid) pH, and the expression of heat-shock protein 70 (HSP70), dinitrophenyl (DNP, an indicator of oxidative stress and ROS), 3-nitrotyrosine protein (NTP, a biomarker of nitrative stress and RNS), catalase (CAT, an antioxidant enzyme), and superoxide dismutase (SOD, an antioxidant enzyme) in the gills and digestive glands of American oyster collected from the southern Gulf of Mexico coast during winter (15oC), spring (24oC), summer (30oC), and fall (27oC). Histological analysis showed increased mucus secretion in both tissues along with the enlargement of lumina in digestive glands; whereas, immunohistochemical analysis showed an increase in HSP70, DNP, and NTP expressions with rising seasonal temperatures, suggesting high seasonal/seawater temperatures cause heat-induced oxidative and nitrative stress in oysters. This was concomitant with a significant decrease in EPF pH and elevated cellular apoptosis in oyster tissues. Interestingly, the expression of CAT and SOD also increased from winter to spring and in fall; however, a significant drop was observed in summer, indicating oyster tissues become defenseless against ROS and RNS mediated oxidative and/or nitrative damage at high seawater temperatures leading to elevated cellular apoptosis. Collectively, we conclude that high seasonal temperatures cause heat-induced oxidative and nitrative stress that disrupts the prooxidant-antioxidant homeostasis leading to increased cellular apoptosis in oysters.