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• Blood-brain barrier plays a central role in a variety of central nervous system diseases and is a drug target. • Mitochondrial oxidative stress disorder in brain microvascular endothelial cells plays a key role in the occurrence and development of blood–brain barrier damage. • Protection of mitochondrial function in brain microvascular endothelial cells is a potential new strategy for the treatment of central nervous system diseases. Blood-brain barrier disruption plays an important role in central nervous system diseases. This review provides information on the role of mitochondrial oxidative stress in brain microvascular endothelial cells in cellular dysfunction, the disruption of intercellular junctions, transporter dysfunction, abnormal angiogenesis, neurovascular decoupling, and the involvement and aggravation of vascular inflammation and illustrates related molecular mechanisms. In addition, recent drug and nondrug therapies targeting cerebral vascular endothelial cell mitochondria to repair the blood–brain barrier are discussed. This review shows that mitochondrial oxidative stress disorder in brain microvascular endothelial cells plays a key role in the occurrence and development of blood–brain barrier damage and may be critical in various pathological mechanisms of blood–brain barrier damage. These new findings suggest a potential new strategy for the treatment of central nervous system diseases through mitochondrial modulation of cerebral vascular endothelial cells. [ABSTRACT FROM AUTHOR]