Huanglian Wendan decoction (HLWDD) has been used for the treatment of symptom of "Re"， one of major causes in diabetes and metabolic disorders， according to the theory of traditional Chinese medicine. The present study aimed at investigating the cerebral protective effects of HLWDD on diabetic encephalopathy (DE)， one of the major diabetic complications. The effects of HLWDD and metformin were analyzed in the streptozocin (STZ) + high-glucose-fat (HGF) diet-induced DE rats by gastric intubation. In the present study， the effects of HLWDD on cognition deficits were investigated after 30-day intervention at two daily dose levels (3 and 6 g·kg). To explore the potential mechanisms underlying the effects of HLWDD， we detected the alterations of neuronal damages， inflammatory cytokines， and impaired insulin signaling pathway in hippocampus of the DE rats. Based on our results from the present study， we concluded that the protective effects of HLWDD against the cognitive deficits and neuronal damages through inhibiting the release of inflammatory cytokines and repairing insulin signaling pathway in hippocampus of the DE rats.