Abstract: To investigate the ameliorative effects and underlying mechanisms of Yiqi Qingnao formula (YQQN) on diabetic encephalopathy (DE). The db/db mice were intragastrically administered with YQQN-L (14.3 g/kg), YQQN-H (28.6 g/kg) and metformin (260 mg/kg) for 8 weeks. Evaluation of the effects of drugs on cognitive function and hippocampal neuronal damage in db/db mice using behavioral tests and histopathological staining. An injury model was established by stimulating HT22 with high glucose (HG) and palmitate acid (PA) to mimic diabetic conditions. Cell viability was assessed using the CCK-8. Cell proliferation was assessed using the EdU. Cell apoptosis was analyzed by flow cytometry. The mRNA and protein expression levels of Bax, Bcl-2, and Caspase-3 were detected by RT-qPCR and Western blot. In addition, using network pharmacology to forecast potential targets and pathways for YQQN in the treatment of DE, and to validate changes in proteins associated with the key signaling pathway. The results showed that YQQN significantly ameliorated cognitive defect and inhibited hippocampal neuronal injury in db/db mice. In vitro, YQQN promoted the proliferation of HT22 induced by HG/PA and reduced apoptosis. The mechanism was related to the inhibition of the excessive activation of the JAK2/STAT3. In conclusion, YQQN attenuates cognitive dysfunction in db/db mice by inhibiting apoptosis via regulating the JAK2/STAT3.