Animals primarily adapt to environmental changes through morphological, behavioral and physiological adjustments. Environmental factors, such as hypoxia, cold, and seasonal resource scarcity, pose significant challenges to animal survival. How to live in a cold and hypoxic environment with limited energy supply is a core survival challenge faced by the high-altitude animals. For mammals, the strategies of physiological adaptations to high-altitude and cold environments mainly included the respiratory and circulatory systems, energy metabolism and thermogenesis, genetic and molecular adaptations, and gut microbiota. In this article, we highlight how animals optimize the morphological changes in structure and function of the oxygen transport chain to enhance oxygen uptake efficiency, how animals maintain energy homeostasis through trade-offs between basal and maximum metabolic rates and thermogenic mechanisms, as well as the molecular genetic basis of hypoxia adaptation and the synergistic role of gut microbiota in aiding host adaptation. The mechanisms of physiological adaptation to high-altitude and cold environments for mammals can offer valuable insights for human adaptation to these environments, which are of great significance for advancing high-altitude medicine and addressing public health issues such as metabolic diseases.