Objective: Ischemic stroke is one of the most common diseases with high mortality and disability. This study was intended to investigate the mechanism of resveratrol (RES) regulating microglia activation through the CD147/matrix metalloproteinase-9 (MMP-9) pathway on ischemic stroke. Methods: The middle cerebral artery occlusion (MCAO) mouse model and oxygen and glucose deprivation (OGD) cell model were established. The behavioral defects, neuronal damage, cerebral infarction volume, and histopathological changes were assessed in MCAO mice. The activation of pro-inflammatory microglia CD86(+)/Iba-1(+) and anti-inflammatory microglia CD206(+)/Iba-1(+) was detected. The expressions of pro-inflammatory microglia markers (CD11b, CD16) and cytokines (TNF-alpha, IL-1 beta, and IL-6) were measured. The activation of the CD147/MMP-9 pathway was detected and its effect on microglia activation was assessed. Results: After RES administration, the neuronal dysfunction, infarct volume, and morphological changes of neurons were improved in MCAO mice. Meanwhile, the motivation of pro-inflammatory microglia and the release of inflammatory factors were repressed. RES suppressed the stimulation of OGD/R microglia and the release of inflammatory factors. The expression of CD147 and MMP-9 in primary microglia was up-regulated. Inhibition of CD147 can reduce pro-inflammatory microglia activation by inhibiting MMP-9 expression. RES inhibited the CD147/MMP-9 axis in OGD/R microglia, and overexpression of CD147 partially reversed the inhibitory effect of RES on the activation and release of inflammatory factors in OGD/R microglia. Conclusion: RES restrained the stimulation of pro-inflammatory microglia by down-regulating the CD147/MMP-9 axis, and thus protected against ischemic brain injury.