Abstract: Cytochrome P450 (CYP450) is the body's most important family of metabolic enzymes and plays an important role in eicosanoid metabolism. High-altitude hypoxia affects the expression and activity of CYP450, which further leads to changes in eicosanoid metabolism. The alteration of eicosanoid metabolites under hypoxia may be an important mechanism for the development of high-altitude diseases and the body's adaptation to hypoxia; however, the specific roles of CYP450 and eicosanoids in the pathophysiological processes of high-altitude diseases, as well as the molecular mechanisms by which hypoxia regulates CYP450, are still unclear. In this paper, we reviewed the changes of CYP450 and eicosanoid metabolites and the mechanisms of CYP450 regulation by cytokines, nuclear receptors, and epigenetic modifications under hypoxic environment and explored the possible mechanisms by which CYP450 and eicosanoid metabolites are involved in the development of high-altitude diseases through the pathways of vasoregulation, inflammation, and oxidative stress. This article aims to provide a new theoretical basis and potential targets for the prevention and treatment of high-altitude diseases.