Homeostasis facilitates maintenance of physiological processes despite extrinsic fluctuations. In aerobic organisms, homeostasis is mainly fueled by metabolism of glucose and lipids, and requires oxygen as a metabolic substrate. Lack of oxygen can therefore trigger an imbalance of homeostasis in vivo. How animals living at high altitude hypoxic conditions can maintain homeostasis between the two types of metabolism remains largely unknown. Here, we establish a 'falconized' mouse model based on an adaptive EPAS1 genetic variant identified from saker falcons (Falco cherrug) on the Qinghai-Tibet Plateau (QTP). We show that homeostasis between glucose and lipid metabolism in the liver under chronic hypoxia is maintained in male falconized mice. This homeostasis is mediated by genetic factors and behavioral plasticity, resulting in higher survival rates even under acute hypoxia than wild type mice. Our study highlights a key role of metabolic homeostasis maintenance for survival in extreme environments, and provides potential targets for the treatment of associated metabolic diseases.