Ischemic stroke is a global health crisis associated with high mortality, long-term disability, and high healthcare costs. Microvascular dysfunction is pivotal in its pathophysiology. The brain microvasculature, far from a passive set of structures, is a complex system participating in multiple biological processes, including controlling angiogenesis, maintaining blood-brain barrier (BBB) integrity, regulating cerebral blood flow (CBF) via neurovascular coupling, managing substance transport, and modulating central nervous system immune responses. Brain microvascular endothelial cells (BMECs) are central to the pleiotropic functions of the brain microvasculature; however, ischemia and hypoxia severely affect BMECs and disrupt microvascular functions. Angiogenesis is dysregulated, the BBB becomes permeable, the regulation of CBF becomes unbalanced, nutrient transport is disrupted, and immune modulation is disrupted. Targeted strategies to safeguard BMECs against ischemic-hypoxic injury have great potential for the treatment of ischemic stroke patients. This review comprehensively outlines the diversity of BMECs under normal conditions, delves into the effects of ischemia and hypoxia on these cells, and explores emerging protective strategies. By integrating these elements, this study offers a holistic perspective on the role of BMECs in ischemic stroke pathophysiology and aims to inspire future research in this crucial field.