Sevoflurane is considered an effective neuroprotector in cerebral ischemia/reperfusion injury (CIRI). Sevoflurane preconditioning in CIRI, however, remains unknown precisely by its molecular mechanism. The middle cerebral artery occlusion reperfusion (MCAO/R) rat model was established, and neurological function was evaluated by Zea-Longa score. Cerebral water content was determined to assess cerebral edema. Brain pathological condition was observed by hematoxylin and eosin staining, the intact changes of rat neurons were observed by Nissl staining, and neuronal apoptosis was measured by TUNEL staining. In addition, miR-192-5p and DICER1 levels were detected by RT-qPCR or Western blot, and the targeting relationship between miR-192-5p and DICER1 was verified by bioinformatics analysis and luciferase reporting experiment. miR-192-5p was up-regulated and DICER1 was down-regulated in MCAO/R rats. Sevoflurane preconditioning could decrease miR-192-5p and promote DICER1 expression. Sevoflurane preconditioning could alleviate brain tissue injury and neuronal apoptosis in MCAO/R rats. DICER1 expression was negatively regulated by targeting miR-192-5p. Elevating miR-192-5p or suppressing DICER1 rescued the protective effect of sevoflurane preconditioning on MCAO/R rats. Sevoflurane alleviates brain injury in MCAO/R rats via miR-192-5p/DICER1 axis.