Despite climate-change challenges, for most aquaculture species, physiological responses to different salinities during ambient extreme cold events remain unknown. Here, European seabass acclimatized at 3, 6, 12, and 30 PSU were subjected to 20 days of an ambient extreme winter cold event (8 °C), and monitored for growth and physiological performance. Growth performance decreased significantly (p < 0.05) in fish exposed at 3 and 30 PSU compared to 6 and 12 PSU. During cold stress exposure, serum Na+, Cl−, and K+ concentrations were significantly (p < 0.05) increased in fish exposed at 30 PSU. Serum cortisol, glucose, and blood urea nitrogen (BUN) were increased significantly (p < 0.05) in fish exposed at 3 and 30 PSU. In contrast, opposite trends were observed for serum protein, lactate, and triglycerides content during cold exposure. Transaminase activities [glutamic-pyruvate transaminase (GPT), glutamic oxaloacetic transaminase (GOT), lactic acid dehydrogenase (LDH), gamma-glutamyl-transaminase (γGGT)] were significantly higher in fish exposed at 3 and 30 PSU on days 10 and 20. The abundance of heat shock protein 70 (HSP70), tumor necrosis factor-α (TNF-α), cystic fibrosis transmembrane conductance (CFTR) were significantly (p < 0.05) increased in fish exposed at 3 and 30 PSU during cold shock exposure. In contrast, insulin-like growth factor 1 (Igf1) expression was significantly lower in fish exposed at 3 and 30 PSU. Whereas, on day 20, Na+/K+ ATPase α1 and Na+/K+/Cl− cotransporter-1 (NKCC1) were significantly upregulated in fish exposed at 30 PSU, followed by 12, 6, and 3 PSU. Results demonstrated that ambient extreme winter cold events induce metabolic and physiological stress responses and provide a conceivable mechanism by which growth and physiological fitness are limited at cold thermal events. However, during ambient extreme cold (8 °C) exposure, European seabass exhibited better physiological fitness at 12 and 6 PSU water, providing possible insight into future aquaculture management options.