Hypoxia and hyperthermia are two connected consequences of the ongoing global change that constitute major threats for coastal marine organisms. In the present study, we used a proteomic approach to characterize the changes induced by hypoxia in individuals of the great scallop, Pecten maximus, subjected to three different temperatures, i.e. 10°C, 18°C and 25°C. We did not observe any significant change induced by hypoxia in animals acclimated at 10°C. Contrastingly at 18°C and 25°C, 16 and 11 protein spots were differentially accumulated between normoxia and hypoxia, respectively. Moreover, biochemical data, i.e. octopine dehydrogenase activity and arginine assays suggests that animals grown at 25°C switched their metabolism towards anaerobic metabolism when exposed to either normoxia or hypoxia, suggesting that this temperature is out of the scallops’ optimal thermal window. In all, 11 proteins could be unambiguously identified by mass spectrometry, involved in protein modifications and signaling (e.g. CK2, TBK1), metabolism (e.g. ENO3) or cytoskeleton (GSN). The potential roles of these proteins in the thermal-dependent response of scallops to hypoxia are discussed.