Extreme weather events are becoming more intense and frequent as a result of climate change. The modulation of hemato-physiological potential as a compensatory response to extreme warm events combined with different salinities is poorly understood. This study aimed to assess the hemato-physiological and molecular response of European seabass, Dicentrarchus labrax exposed to extreme warm temperature (33 °C) after prior acclimatization at 32 psu, 12 psu, 6 psu, and 2 psu water. Fish were acclimated to 32 psu, 12 psu, 6 psu, and 2 psu followed by 10 days extreme warm (33 °C) exposure. Along with growth performance and survival, hemato-physiological response and molecular response of fish were recorded. Fish held at 32 psu and 2 psu exhibited significantly lower growth performance and survival than those at 12 psu and 6 psu (p < 0.05). Red blood cells (RBC), hematocrit, and hemoglobin content were significantly decreased, while white blood cells (WBC), erythrocytic cellular abnormalities (ECA) and erythrocytic nuclear abnormalities (ENA) were found to increase significantly in 32 psu and 2 psu fish (p < 0.05). Plasma lactate was found to increase significantly in 32 psu fish on day 10 (p < 0.05). Activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and TNF-α expression increased significantly in 32 psu and 2 psu fish (p < 0.05). Most of the repeated measured parameters indicated limited acclimation capacity during the extreme warm exposure at all four salinity groups. However, overall results indicate that European seabass acclimatized at 12 psu and 6 psu salinities, can cope better during extreme warm exposure (33 °C).