Climate change and eutrophication increase the frequency and duration of heat waves (HWs) along with diurnal oxygen and pH fluctuations (FH) in coastal ecosystems. Mussels (Mytilus edulis) are marine ecosystem engineers commonly exposed to temperature, pH and oxygen fluctuations and an excellent model species for investigating the cumulative effects of these stressors on survival and physiological performance of keystone benthic organisms. Here, we evaluated whether a 3-week exposure to FH would alter mussels’ responses to a HW scenario. We examined the physiological responses including respiration (RR), clearance (CR) and nitrogen excretion (ER) rates, and byssus production, as well as biochemical indicators of energy status and oxidative stress in the gills of mussels exposed to well-oxygenated or FH conditions before and after 24h, 1 and 2 weeks of HW (1826°C). ER and RR increased transiently during the HW, and FH exposure prevented the return to baseline (ER) or slight decrease (RR) observed after 2w HW in normoxia. A parallel increase of the protein concentrations between 24h and 1w HW indicate that protein turnover is linked to the thermal acclimation. Decrease in the lipid peroxidation levels was found after 1w HW, indicating adjustments of redox balance after prolonged warming, although FH altered the antioxidant upregulation pattern. Mussels CR decreased, but cellular energy status remained stable during HW. These results highlight that FH acclimation affects the physiological responses of M. edulis to HW and could reduce mussels’ resilience to the intense scenarios predicted for future Baltic Sea coasts.