The response of aquatic species to heat and hypoxia is to enter a state of low metabolism, reduce metabolic rate, suspend development and reproduction, and survive in the critical ecological changes. The role of epigenetics response to the environmental stresses is currently being revealed, but the specific regulation mechanism is not precise. In this study, the whole genome methylation of the respiratory tree of Apostichopus japonicus under heat, hypoxia, and heat-hypoxia conditions (designed as HT, LO, and HL groups) was determined to study the regulation mechanism.