Climate change due to increasing CO emissions results in the increase in water temperatures, which is accompanied by the decrease in pH and salinity levels of the ocean. Ocean acidification reflects the gradual pH reduction due to changes in the carbon chemistry, which is caused by the increase in anthropogenic CO emissions. The subsequent changes in the water temperatures and carbon chemistry of the oceans affect the survival and distribution of aquatic animals. In this study, we analyzed the levels of cortisol, superoxide dismutase, catalase, and caspase-3 in the plasma of juvenile olive flounder Paralichthys olivaceus under combined hyposalinity and acidification. To evaluate the physiological response to these changes, the superoxide dismutase activity and apoptosis were analyzed in the liver cells. Hyposalinity caused oxidative stress and cell damage, while also activating the antioxidant system. Environmental acidification affected the stress response and antioxidant mechanism of P. olivaceus in the early stage of acclimation but did not appear to exceed hyposalinity stress. These findings suggest that a hyposaline environment may be a stronger environmental stressor than an acidifying environment for P. olivaceus, and will help understand the capacity of P. olivaceus to cope with expected future ocean acidification.