High-altitude hypoxia affects the human respiratory, central nervous, cardiovascular, and endocrine systems. These outcomes affect the expression of cytochrome P450 (CYP), the most important family of metabolic enzymes in the body that is involved in the metabolism of both exogenous and endogenous substances (such as arachidonic acid, vitamins, and steroids). Hypoxia influences CYP expression and activity, mediating changes in drug and endogenous substance metabolism, with endogenous metabolites playing a significant role in controlling high-altitude diseases. However, the mechanisms regulating CYP changes under hypoxic conditions and the effects of CYP changes on drug and endogenous metabolism remain unclear. We explored how changes in CYP expression and activity during hypoxia affect the metabolism of drugs and endogenous substances, such as arachidonic acid, vitamins, and steroid hormones, and how CYPs are controlled by nuclear receptors, epigenetic modifications, cytokines, and gut microbiota during hypoxia. Special attention will also be given to the complex role of CYP and its metabolites in the pathophysiology of high-altitude diseases to provide valuable insights for plateau medicine research. SIGNIFICANCE STATEMENT: Cytochrome P450 is a class of monooxygenases that metabolize xenobiotics and endogenous substances. Hypoxia affects the expression and activity of cytochrome P450, and this in turn affects the metabolism of drugs and endogenous substances, leading to altered clinical efficacy and the development of hypoxia-associated diseases. A comprehensive understanding of the changes and regulatory mechanisms of cytochrome P450 under hypoxic conditions can improve therapeutic protocols in hypoxic environments and provide new ideas for the targeted treatment of hypoxic diseases.