This study evaluated the impact of 4 weeks of periodic hypoxia stress on hemogram, oxidative stress markers, immune markers, gene expression of hypoxia-responsive proteins, heat shock proteins, and inflammation-related genes, as well as the structural integrity of spleen tissue in Oreochromis niloticus (Nile tilapia). To further investigate immune competence, fish were challenged with Aeromonas sobria to assess their ability to combat bacterial infections after hypoxia exposure. Additionally, the potential modulatory effects of dietary replacement with camel whey protein hydrolysate (HPCW) at a 75-g/kg diet were scrutinized. Fish were divided into four groups, each with four replicates (10 fish per replicate), and fed either a basal diet or an HPCW-supplemented diet. The groups are control, HPCW, hypoxia group, and hypoxia + HPCW. The study demonstrated that periodic hypoxia triggered pronounced immune and oxidative stress responses in Oreochromis niloticus, as evidenced by significantly (P < 0.001) increased nitric oxide levels, lysozyme activity, complement-3, and oxidative stress markers, along with decreased antioxidant enzyme activity compared to the control. Molecular analysis revealed the upregulation of stress- and inflammation-related genes (il-1β, tnf-α, hif1-α, HSP70, HSP60, and HSP90) in the spleen tissue of hypoxia-exposed fish by 4.5-fold, 2.51-fold, 7.8-fold, 7.46-fold, 5.18-fold, and 7.5-fold, respectively, compared to the control group. Histopathological assessment confirmed tissue damage, including vascular congestion, hemorrhages, erythroid and lymphoid hyperplasia, endothelial changes, and increased melano-macrophage centers. Importantly, dietary supplementation with hydrolyzed camel whey protein (HPCW) significantly mitigated these effects. HPCW-supplemented fish during hypoxic conditions exhibited improved immune function, enhanced antioxidant capacity, reduced gene expression of inflammatory markers, and less splenic tissue damage compared. Moreover, HPCW-fed fish showed higher survival rates following Aeromonas sobria challenge. These findings highlight the novel role of HPCW as a functional feed additive that enhances fish survival and immunity under periodic hypoxia stress.