High-altitude hypoxia affects 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 involved in the metabolism of both exogenous and endogenous substances. Hypoxia influences CYP expression and activity, mediating changes in drug and endogenous substance metabolism, with endogenous substance metabolites playing a substantial role in controlling high-altitude diseases. However, the mechanisms that regulate CYP changes under hypoxic conditions and the effects of CYP changes on drug and endogenous metabolism remain unclear. We examined how CYP expression and function change during hypoxia and how they are controlled by nuclear receptors, epigenetic modifications, cytokines, and gut microbiota during hypoxia. This was done to understand how CYP affects the metabolism of drugs and endogenous substances, such as arachidonic acid, vitamins, and steroid hormones during hypoxia, and to determine how CYP and its metabolites are involved in the pathophysiology of diseases linked to high-altitude hypoxia.