The California mussel, Mytilus californianus, is a model organism for the physiological adaptations to the rocky intertidal zone. Due to their sessile nature, their physiological responses to environmental stressors (like heat stress) provide indication of when further climate change starts to be detrimental. Sirtuins are involved in regulating antioxidant systems, such as the glutathione system, during stress through post-translational modifications. Previous studies suggest sirtuins are activated by caloric restriction and are involved in the heat shock response of mussels. In this study, we investigated if sirtuins affected the stress response of M. californianus (i.e. the antioxidant capacity of the glutathione system) to heat stress. Furthermore, we investigated if algal ration affected the mussels’ response to these stressors. Mussels were fed a low or high algal food ration for 3 wk before exposure to one of four conditions: (A) acute aerial heat stress (33°C), (B) sirtuin inhibition, (C) acute heat shock following sirtuin inhibition, or (D) no treatment. Confirming previous experiments, sirtuin activity was higher in mussels fed a low food ration compared to the high ration mussels. Additionally, we observed an increase in SIRT5 abundance 4 hours after sirtuin inhibition (regardless of ration) and increased GSH:GSSG in mussels acclimated to the low food ration following exposure to either acute heat stress or sirtuin inhibition (but not both) compared to high food ration mussels. Our findings suggest that sirtuins, possibly activated by low food intake and/or acute heat stress, are involved in the mussels’ glutathione system, and may be important regulators of the oxidative stress response.