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This study investigates the immunological and growth effects of Vitamin C and Zinc supplementation on Nile tilapia (Oreochromis niloticus) subjected to cold water stress. Nile tilapia fingerlings were housed in eight 20-gallon tanks at Purdue University, acclimated to 26 ± 2°C water conditions before the experiment. The tilapia was divided into groups with varying water temperatures and feed supplements: control fish in warm water, and experimental groups in cold water with increased levels of Vitamin C and Zinc. Stress was induced by lowering the water temperature to 15 ± 2°C in four tanks, while the remaining tanks were kept at the optimal growth temperature. Results demonstrated that Vitamin C and Zinc supplementation significantly enhanced immune response and muscle regeneration in cold-stressed tilapia, allowing them to achieve growth rates comparable to those of control fish in optimal warm water conditions. These findings highlight the potential benefits of combined Vitamin C and Zinc supplementation in improving the immune response and growth performance of tilapia under suboptimal temperature conditions.