Alterations in the M1/M2 polarization phenotype significantly affect disease progression. Antioxidant and anti-inflammatory protective effects of resveratrol (Res) have been demonstrated. This paper tested the hypothesis that Res could protect against cerebral ischemia-reperfusion injury (CI/RI) by modulating microglial polarization via the miR-450b-5p/KEAP1/Nrf2 pathway. Rats were first treated with Res and adenovirus that interfered with miR-450b-5p or KEAP1, and then established a middle cerebral artery occlusion-reperfusion model using modified nylon sutures. Rats were then evaluated for neurological and behavioral functions, and markers of M2 microglia were detected by immunofluorescence staining. Additionally, the signature patterns of miR-450b-5p, KEAP1, and Nrf2 were determined. The collected data demonstrated that Res exerted neuroprotective effects in CI/RI by promoting microglial M2 polarization. Additionally, Res could regulate the Nrf2 pathway by targeting KEAP1 by up-regulating miR-450b-5p. Up-regulating miR-450b-5p or down-regulating KEAP1 could further promote the protective effect of Res, while down-regulating miR-450b-5p or up-regulating KEAP1 worked oppositely. Our study demonstrates that Res exerts neuroprotective effects on microglial M2 polarization through the miR-450b-5p/KEAP1/Nrf2 pathway during CI/RI.