Rationale <p>Diabetic encephalopathy (DE) remains a severe complication of diabetes in central nervous system with limited effective therapy.</p> Objectives <p>This study investigated the beneficial effect of senegenin on DE and its possible mechanisms.</p> Methods <p>Type 2 diabetes mellitus mouse model and high-glucose (HG)-stimulated PC-12 cells were used as the in vivo and in vitro DE models. Learning and memory ability was evaluated by MWM test. Pathological changes in the brain tissues were determined by HE staining. Cell viability was detected by CCK-8. Mitochondrial membrane potential was measured by JC-1 probe. Target protein levels were assessed by Western blotting. Nucleotide-binding domain-like receptor protein 3 (NLRP3) expression was observed by immunofluorescent staining.</p> Results <p>Cognitive impairment and obvious pathological changes were found in DE mice, which were effectively attenuated by senegenin treatment. In addition, senegenin induced mitophagy and maintained homeostasis of mitochondrial dynamics to relieve mitochondrial dysfunction. Moreover, NLRP3 inflammation activation induced by DE was inhibited by senegenin. Finally, inhibition of mitophagy counteracted senegenin-mediated inactivation of NLRP3 inflammation and neuroprotection.</p> Conclusions <p>Senegenin relieved diabetic encephalopathy via inducing mitophagy to inactivate NLRP3 inflammasome. Senegenin might be an effective therapy for treating DE.</p>