This study investigated the impacts of Camel whey protein hydrolysate (CPH) supplementation on hepatocellular damage in Nile tilapia (Oreochromis niloticus) under hypoxic stress condition. Specifically, to elucidate the fundamental impacts of chronic hypoxia stress on the expression of key genes, cyp1a, hif-a, pk, cpt-1, pdk, and hsp70 in Oreochromis niloticus. Additionally, we aim to explore the involvement of the Nrf-2-Keap-1 expression as a potential mechanism through which chronic hypoxia stress may induce hepatic tissue damage. Also, other genes that catalyze the oxidative decarboxylation of pyruvate and glucose metabolism (pdk-1, cpt-1, pk, and ldh) reflect liver stress and vitality in hypoxic and normoxic conditions in Nile tilapia. Four groups of fish, each containing 40 fish (17.40 ± 0.50 g), were included for 4 weeks. The experimental diets embraced basal and 75 g CPH/kg enriched diets. Two fish groups persisted in normoxic conditions, while the others were restrained in hypoxic conditions (DO around 1.7 mg/L). The results revealed that a fortified diet with CPH significantly reversed the hypoxia-induced reduction in the antioxidants (CAT, GSH, and SOD), liver enzymes, and lipid profile changes. However, the hypoxic states caused the downregulation of cyp1a1 but up-regulated the expression of hif-a, and hsp-70 via nrf-2-keap-1 signaling pathways. Moreover, hypoxia stress-induced histopathological alterations in the fish liver tissue were substantially reversed by CPH dietary supplementation. These results concluded that CPH is a beneficial dietary supplement for mitigating the impacts of hypoxia stress on the liver.