This study aimed to investigate the protective effect of sevoflurane postconditioning on cerebral ischemia-reperfusion (CIR) injury in rats and the mechanisms. Fifty-four male SD rats were randomly divided into sham-operated group, CIR group and CIR+sevoflurane postconditioning (CIR+SEV) group, 18 rats in each group. In CIR group and CIR+SPC group, the CIR model was established by ischemia for 120 min followed by reperfusion for 72 h. The CIR+SPC group received inhalation of sevoflurane with 1.0 time minimum alveolar concentration at the beginning of reperfusion, and the inhalation was continued for 30 min. Results showed that, after 72 h from ischemia, compared with CIR group, in CIR+SPC group the neurological deficit score was decreased, the brain water content and percentage of brain infarction area were decreased, the tumor necrosis factor-alpha and interleukin-1 beta levels were decreased, the brain tissue superoxide dismutase level was increased, the malondialdehyde and reactive oxygen species levels were decreased, and the brain tissue nuclear factor-erythroid 2 related factor 2 and heme oxygenase-1 protein expression levels were increased (all P < 0.05). Sevoflurane postconditioning can mitigate the brain injury in CIR in rats, which may be related to its resistance of inflammatory response and oxidative stress and regulation of nuclear factor-erythroid 2 related factor 2/heme oxygenase-1 signal pathway.