Hypoxia is among the most prevailing stressors in aquaculture and exerts negative impacts on fish health and metabolism; hence, the search for dietary strategies that mitigate such impacts has been of prime importance. In the present work, chronic daily periodic hypoxic stress on Oreochromis niloticus was induced, together with the protective role of camel whey protein hydrolysate added at 75 g/kg in the diet. The present study has focused on kidney function, serum ions, cortisol, glucose, and markers of oxidative stress. Expression of hypoxia-inducible factor (HIF-α) and inflammation-related genes in the kidney and key genes involved in metabolic and ion-regulatory functions in the gills were assessed. Fish was divided into four groups: a control group maintained in normoxic conditions with a basal diet; a hypoxic group subjected to daily 6-h hypoxic periods at DO ∼1.7 mg/L with the basal diet; a CW group fed camel whey protein hydrolysate under normoxic conditions; and a combined HPX + CW, which received CW-replaced diet (75 mg/kg diet) during HPX conditions. The hypoxic conditions were achieved by stopping aeration and covering the aquaria with a plastic film daily for 6 h, while the temperature and ammonia levels in the water were regularly checked during the experimental period of four successive weeks. The results revealed renal tissue damage with increased levels of oxidative biomarkers. On the molecular level, down-regulation of SDH; and the up-regulation expression of hypoxia and inflammation-related genes (HIF-α, Interleukin-1β (IL-1β), Collagen, type I, alpha 1(COL1A1), and Transforming factor beta-1 (TGF-β1)) in the kidney. Also, histopathological alterations were observed including, nephropathic alterations and hyperplasia of gill epithelium, with enhancement in the immunoreactivity to TNF-α and Caspase-3. In turn, CW supplementation significantly improved all these parameters and hence can be used as an anti-stress dietary supplement to enhance resilience against hypoxic challenges.