Aims: The aim of this study was to examine the effects of sericin on diabetic cognitive impairment (DCI) in rats based on neuroinflammation. Methods: SD rats were firstly fed with high sugar and high fat diet for 4 weeks, and then injected with 50 mg/kg streptozotocin intraperitoneally to establish a diabetic model. The diabetic rats were randomly divided into 3 groups and treated with distilled water (n=10), 500 mg/kg (n =10) and 1000 mg/kg (n=20) sericin, respectively, by gavage once a day for 8 weeks. Before the end of the trail, 10 rats in the 1000 mg/kg sericin group were injected with 10 μg EX527 (a SIRT1 inhibitor) into the lateral ventricles once every other day for 5 times. Results: Treated with sericin significantly reduced the fasting blood glucose, improved DCI in rats. Sericin significantly inhibited of neuroinflammation, reduced the expression of NLRP3, TXNIP proteins and reduced cell apoptosis, while increased the expression of SIRT1 protein in the hippocampus of diabetic rats. After inhibiting SIRT1 with EX527, the above effect of sericin on DCI rats was weakened. Conclusions: These results indicated that sericin may block DCI progression in rats by inhibiting TXNIP/NLRP3 neuroinflammation and neuronal apoptosis though SIRT1.