Purpose:　This　study　aimed　to　assess　the　protective　effect　of　a　clinical　dose　esketamine　on　cerebral　ischemia/reperfusion　(I/R)　injury　and　to　reveal　the　potential　mechanisms　associated　with　microglial　polarization　and　autophagy.　Methods:　Experimental　cerebral　ischemia　was　induced　by　middle　cerebral　artery　occlusion　(MCAO)　in　adult　rats　and　simulated　by　oxygen-glucose　deprivation　(OGD)　in　BV-2　microglial　cells.　Neurological　and　sensorimotor　function,　cerebral　infarct　volume,　histopathological　changes,　mitochondrial　morphological　changes,　and　apoptosis　of　ischemic　brain　tissues　were　assessed　in　the　presence　or　absence　of　esketamine　and　the　autophagy　inducer　rapamycin.　The　expression　of　biomarkers　related　to　microglial　M1　and　M2　phenotypes　in　the　ischemic　brain　tissues　was　determined　by　immunofluorescence　staining　and　RT-qPCR,　and　the　expression　of　proteins　associated　with　autophagy　and　the　AKT　signaling　pathway　in　the　ischemic　brain　tissues　was　assayed　by　Western　blotting.　Results:　Esketamine　alone　and　esketamine　combined　with　rapamycin　alleviated　neurological　impairment,　improved　sensorimotor　function,　decreased　cerebral　infarct　volume,　and　mitigated　tissue　injury　in　the　MCAO　rats.　Importantly,　esketamine　promoted　microglial　phenotypic　transition　from　M1　to　M2　in　both　the　MCAO　rats　and　the　OGD-treated　BV-2　microglia,　induced　autophagy,　and　inactivated　AKT　signaling.　Furthermore,　the　effects　of　esketamine　were　enhanced　by　addition　of　autophagy　inducer　rapamycin.　Conclusion:　Esketamine　at　a　clinical　dose　attenuates　cerebral　I/R　injury　by　inhibiting　AKT　signaling　pathway　to　facilitate　microglial　M2　polarization　and　autophagy.　Furthermore,　esketamine　combined　autophagy　inducer　can　provide　an　improved　protection　against　cerebral　I/R　injury.　Thus,　this　study　provides　new　insights　into　the　neuroprotective　mechanisms　of　esketamine　and　the　potential　therapeutic　strategies　of　cerebral　I/R　injury.