<p>Ischemia–reperfusion injury (IRI) is a critical issue in the prevention and treatment of ischemic stroke. Inhalational anesthetics have been proven to have neuroprotective effects and sevoflurane is currently the most commonly used inhaled anesthetic in the clinic. However, the effects and underlying mechanism of sevoflurane on cerebral IRI have not been fully elucidated. In this study, oxygen–glucose deprivation model was established in primary mouse cortical neurons and HT22 cells, while the middle cerebral artery occlusion model was established in mice. Using laser speckle imaging, TTC staining, HE staining, Nissl staining, flow cytometry, calcium imaging and neurologic deficit scoring, we found that sevoflurane post-conditioning (SPC) significantly increased cerebral blood flow, reduced the infarct volume, alleviated neuronal pathological damage, promoted the survival of cortical neurons, reduced cell apoptosis, enhanced calcium responses and decreased the neurologic deficit scores after IRI. The results of RNA sequencing, Western blot, co-immunoprecipitation, TUNEL staining, immunofluorescence, transmission electron microscopy imaging, MPTP measurement, MMP detection, and ATP production measurement showed that the sonic hedgehog (Shh) signaling pathway crosstalk with Hippo-YAP signaling pathway, and the Shh-YAP1 pathway regulated mitochondrial dynamics and mitochondrial ultrastructure and function. In addition, SPC affected the phosphorylation and SUMOylation of dynamin-related protein 1 (Drp1), and there was an interaction between the phosphorylation and SUMOylation of Drp1. In conclusion, this study revealed that SPC might affect the phosphorylation and SUMOylation of Drp1 through the Shh-YAP1 signaling pathway, regulating mitochondrial dynamics, reducing cell apoptosis and ameliorating IRI. These findings offer new insights into the therapeutic strategies for ischemic stroke.</p> Graphical abstract <p></p>