Abstract: After ischemic stroke, microglia play a “double-edged sword” role in neuroinflammation, aggravating injury while also facilitating repair. This review summarizes the dual mechanistic roles of microglia in ischemic stroke and the progress in microglia-targeted therapies. Microglial phenotypic polarization demonstrates spatiotemporal heterogeneity: in the acute phase, M1-type microglia (with high expression of CD86 and inducible nitric oxide synthase, iNOS) in the ischemic core promote inflammation, whereas in the subacute phase, M2-type microglia (with high expression of CD206 and arginase-1, Arg-1) in the penumbra facilitate tissue repair. Intermediate subtypes such as lipid droplet-rich microglia (LDRM) also exist. Mitochondrial dysfunction, enhanced glycolysis, and disordered lipid metabolism jointly drive neuroinflammation. Microglial functions are partially mediated by extracellular vesicles (EVs) released by microglia, which serve as key intercellular communication vehicles; EVs derived from different cellular sources regulate pathological progression via their bioactive cargos. Furthermore, microglia participate in the fine regulation of neurogenesis through close interactions with hippocampal neural stem cells (NSCs): the M1 phenotype inhibits regeneration, whereas the M2 phenotype supports survival and differentiation. Current microglia-targeted therapeutic strategies mainly include genetic modulation (e.g., overexpression of sortilin-related receptor with A-type repeats; use of peroxisome proliferator-activated receptor-α agonists), engineered EV-based therapies, and metabolic interventions. However, clinical translation faces challenges such as spatiotemporal heterogeneity. Future research should focus on spatiotemporally precise interventions to facilitate the clinical application of these strategies.