Abstract: Objective: This study aimed to develop a functional beverage using turnip (Brassica rapa) and sea buckthorn (Hippophae rhamnoides), which were traditional medicinal and edible plants, and to investigate its ameliorative effect and potential mechanisms against hypoxia-induced injury. Methods: The formulation of the turnip-sea buckthorn compound beverage was optimized using single-factor experiments and response surface methodology. After optimization, mouse models of normobaric hypoxia and sodium nitrite poisoning were established. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) in heart, brain, and lung tissues were measured. Hematoxylin-eosin (HE) staining and Western blot analysis were performed to assess the expression levels of hypoxia-inducible factor-1α (HIF-1α) and interleukin-6 (IL-6). Results: The optimal formulation was determined to be 22.0% sea buckthorn juice, 1.0% turnip extract, 7.5% high-fructose syrup, and 0.1% citric acid, which yielded a sensory score of 80.5±1.3. The physicochemical indices (including soluble solids at 8.00%, total sugar at 9.12%, and total acid at 3.31 g/L) all complied with relevant national standards. In animal studies, administration of the low-, medium-, and high-dose groups (8.45, 16.90, and 33.80 g/kg·d, respectively) resulted in a significant extension of survival time under normobaric hypoxia by 19.92%, 19.31%, and 18.97% (P<0.05), respectively. Concurrently, the beverage treatment enhanced the activities of antioxidant enzymes (SOD, CAT, and GSH-Px) while reducing the MDA content in the heart, brain, and lung tissues. Western blot analysis further revealed that the compound beverage ameliorated oxidative stress and modulated the energy metabolism pathway via the suppression of HIF-1α protein expression and IL-6 release. Conclusion: The optimized turnip-sea buckthorn compound beverage effectively improved hypoxia tolerance. The underlying mechanism may be associated with the enhancement of antioxidant capacity and inhibition of the HIF-1α/IL-6 inflammatory pathway. These findings provide a theoretical basis for the development of functional foods aimed at mitigating hypoxia-induced damage.