Fluctuations in dissolved oxygen (DO) levels in aquaculture systems can induce hypoxia and hypercapnia, leading to physiological disruptions in fish. This study aimed to assess the effectiveness of dietary supplementation with camel whey protein hydrolysate (CWP) in mitigating the effects of hypoxia stress on physiological limits in Oreochromis niloticus. To attain this, firstly, we applied an in silico study to predict the protein–protein interaction of camel’s α-lactalbumin, lactoferrin, and lysozyme with tilapia’s NF-κB, TNF-α, IL-1β, IL-6, and IL-8 via PDBsum Generate. Then we planned for the in vivo trial; 160 obviously healthy Nile tilapia (average16.40 ± 0.40 g) were divided into four groups in four replicates for a 30-day feeding experiment. The control group (normoxic) received a basal diet without supplementation, maintaining DO levels > 90%, while the CWP group received a basal diet supplemented with 75 g/kg CWP under normoxic conditions. The hypoxic group was exposed to 20% DO levels (approximately 1.7 mg/L), and the hypoxia + CWP group received a CWP-supplemented diet under hypoxic conditions. Results exhibited a protein–protein interaction between the CWP and targeted proteins related to inflammation of the gut in Nile tilapia indicating its efficacy to protect the tissue against hypoxia stress-induced gut inflammation. Also, CWP dietary supplementation significantly alleviated hypoxia-induced impairments in weight gain, growth rate, and feed conversion ratio (FCR). Moreover, CWP consumption restored the depleted activities of intestinal lipase, trypsin, and amylase induced by hypoxia. Additionally, CWP supplementation normalized disrupted serum leptin and growth hormone levels caused by hypercapnia stress. Furthermore, CWP significantly corrected the pathological alterations, depletion of antioxidants, and increased lipid peroxidation product (MDA) in intestinal tissues induced by low DO levels. Furthermore, CWP supplementation restored the expressions of tight junction protein-coding genes (zo-1, zo-2, claudin-4, and occludin) and inhibited intestinal inflammation by modulating the MAPK/PI3K/Akt signaling pathway in hypoxic fish. In conclusion, dietary supplementation with CWP shows promise in mitigating the detrimental events of hypoxia stress on fish growth, likely through its antioxidant activity and regulation of intestinal tight junction proteins, along with its anti-inflammatory potential and significantly enhances the activities of key digestive enzymes such as amylase, lipase, and trypsin. This enzyme potentiation plays a crucial role in promoting growth in Oreochromis niloticus.