Background: Obesity is recognized as a primary risk factor for cerebral ischemia, which has shown a significant increase in its incidence among obese patients. The exact mechanism by which obesity exacerbates cerebral ischemic injury is not fully understood though. The present study validated the hypothesis that obesity mediates pyroptosis by the AGEs/RAGE signaling pathway to exacerbate cerebral ischemic injury. Methods: Leptin receptor knockout ( Lepr (-/-) ) rats were used in this study to construct an obesity model, and the middle cerebral artery occlusion (MCAO) models of ischemic stroke were established in Lepr(-/- ) obese rats and their wild-type (WT) littermates respectively. Zea-Longa score, TTC and H&E staining were utilized to evaluate the neurological impairment. Western Blot, immunohistochemistry, and immunofluorescence were used to detect protein expressions. Transmission electron microscopy was used to observe the pores in the neuronal cell membrane in the ischemic penumbra cortex. Results: Compared with WT littermates, Lepr(-/-) obese rats exhibited exacerbated neuronal injury after MCAO, with higher expressions of NLRP3 inflammasome and pyroptosis-related proteins in the cortical tissue of the penumbra. Moreover, more GSDMD pores were observed on the neuronal cell membranes of Lepr(-/-)obese rats according to the electron microscopy. Inhibition of NLRP3 inflammasome expression with MCC950 inhibited neuronal pyroptosis after cerebral ischemia in Lepr(-/-) rats, thus reducing neuronal injury. We also found that compared with WT littermates, the levels of AGEs and RAGE in the cortex of Lepr-/-obese -/- obese rats are significantly higher, with further increase after cerebral ischemia. Inhibition of AGEs/RAGE signaling pathway with FPS-ZM1 reduced the NLRP3 inflammasome-mediated neuronal pyroptosis in Lepr-/-obese -/- obese rats, thereby mitigating the neuronal damage after cerebral ischemia. Conclusion: The AGEs/RAGE signaling pathway is involved in the exacerbation of cerebral ischemic injury in Lepr-/-obese -/- obese rats via regulating NLRP3-mediated neuronal pyroptosis.