The eastern oyster Crassostrea virginica has a remarkable ability to withstand low oxygen conditions; however, many of the biochemical mechanisms by which that tolerance is accomplished remain poorly understood. In addition, little is known about hypoxia tolerances and adaptations of the Asian oyster Crassostrea ariakensis. By comparing these closely related species, we may learn more about the physiological mechanisms responsible for the hypoxia tolerance of C. virginica. We assessed the time to mortality and gaping responses in both species during hypoxia. Adult C. ariakensis died earlier than C. virginica and gaped more often and wider than C. virginica. Gaping by either species was associated with acidification of the ambient seawater. We also compared the hemolymph pH of emersed and clamped C. virginica and C. ariakensis between 0 h and 24 h. In both species, hemolymph pH declined over time, and C. ariakensis hemolymph became significantly more acidic throughout the study period than that of C. virginica. The infection levels of Perkinsus marinus observed in our samples were not correlated with hemolymph pH changes in either species. Our findings demonstrate fundamental differences in survival and suggest important physiological differences exist between these species.