Abstract: Hypoxia-related diseases, such as altitude sickness, acute lung injury, and heart failure, have emerged as significant public health challenges worldwide and are strongly associated with increased mortality risks. These conditions tend to cause functional impairment and structural alterations in multiple organs, primarily due to inadequate oxygen supply or the inability of tissues to utilize oxygen effectively. To elucidate the pathophysiological mechanisms underlying hypoxia-associated diseases and to explore potential therapeutic strategies, researchers have employed animal models to conduct extensive mechanistic studies and drug development trials. In this review, we provide a comprehensive overview of the methods used to construct animal models for various hypoxia-related diseases. We made a thorough evaluation of the strengths, weaknesses, limitations, and applicability of each approach. In particular, we focus on modeling strategies for key pathologies such as altitude sickness, acute lung injury, pulmonary hypertension, and heart failure, discussing their respective advantages and restrains. Furthermore, we examined the potential application of gene editing technologies in optimizing animal models, especially its role in enhancing the accuracy and reproducibility of the models. The integration of these advanced technologies holds great promise for developing animal models with improved specificity and simulation of key features of diseases, which will serve as a solid foundation for basic research, drug screening, and preclinical trials concerning hypoxia-related diseases. Herein, we present a systematic summary and future outlook of animal models for hypoxia-related diseases, ultimately providing theoretical support for developing clinical treatment strategies and improving patient outcomes.