Abstract: Objective: To explore the neuroprotective effect and mechanism of soy isoflavones (SI) on cerebral ischemia-reperfusion injury (CIRI) by inhibiting NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome-mediated neuronal pyroptosis. Methods: Sixty healthy Sprague-Dawley (SD) rats were randomly divided into sham group, model group, SI group and SI+Nigericin group. Rats in the SI group were pretreated with intragastric administration of SI (120 mg/kg) once daily for 21 consecutive days. The middle cerebralartery occlusion (MCAO) rat model was established by the suture-occluded method, and reperfusion was induced by withdrawing the suture after 2 hours of ischemia; the sham group only underwent vascular separation without suture insertion. Five minutes before reperfusion, rats in the SI+Nigericin group were injected with Nigericin (1 mg/kg) via the tail vein. Twenty-four hours after reperfusion, the severity of brain injury was assessed by neurological deficit score, brain water content (dry-wet weight method), 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, and hematoxylin-eosin (HE) staining. The expression of pyroptosis-related proteins was measured by immunofluorescence staining and western blotting. The serum levels of interleukin (IL)-1β, IL-18 and the activity of lactate dehydrogenase (LDH) were measured by enzyme-linked immunosorbent assay (ELISA). Results: Compared with the model group, the SI group exhibited significantly reduced neurological deficit scores, brain water content, cerebral infarct volume (P＜0.001), as well as obviously alleviated cortical pathological injury. In the SI group, the protein expression levels of NLRP3, Gasdermin D (GSDMD), GSDMD N-terminal domain (GSDMD-N), caspase-1, cleaved caspase-1, IL-18, IL-1β and IL-1β p17 were downregulated; serum IL-1β and IL-18 contents as well as LDH activity were reduced (all P＜0.05), and the fluorescence signals of NLRP3 and GSDMD-N in brain tissues were obviously weakened. Nigericin could partially reverse the above protective effects of SI (P＜0.05). Conclusion: SI reduces neuronal pyroptosis by inhibiting NLRP3 inflammasome activation, thereby effectively alleviating CIRI and exerting neuroprotective effects.