To explore the protective effects of 6-shogaol (6-SH) against cerebral is chemia-reperfusion injury (CIRI) in rats, molecular docking was utilized to investigate the spontaneous binding ability of 6-SH with microRNA-26a-5p (miRNA-26a-5P). Dual luciferase reporter gene assays were employed to validate the targeted relationship between miRNA-26a-5p and death associated protein kinase 1 (DAPK1). The CIRI rat model was induced using the suture method, with male SD rats randomly assigned to sham surgery, model, and 6-shogaol groups. Improved neurological function scoring was conducted 72 hours post-CIRI, accompanied by Triphenyltetrazolium chloride (TTC) staining. Post-scoring, brain tissue specimens were collected for hematoxylin-eosin (HE) staining to observe neuronal pathological damage. Transmission electron microscopy was utilized to examine neuronal ultrastructure and autophagy. Immunofluorescence was employed for the detection of autophagic markers, and real-time fluorescence quantification, along with protein immunoblotting, were performed to assess proteins and genes related to autophagy and calcium overload. The results indicate that 6-shogaol can upregulate miRNA-26a-5p expression, inhibit DAPK1 expression, and alleviate excessive autophagy and calcium overload after CIRI in rats, showcasing its neuroprotective properties.