Although previous studies showed that exercise can improve cognitive dysfunction in type 2 diabetes (T2DM), the underlying mechanism remains unclear. Sirtuin 1 (SIRT1) has been shown to play a role in regulating inflammatory responses in the brain and increasing BDNF expression. This study investigated the effects of treadmill exercise on the hippocampal inflammatory response and BDNF expression in a T2DM mice model. We also tested whether these effects are SIRT1-dependent. In this study, C57BL/ 6 mice were used to construct T2DM model by a high-fat diet and STZ injection. We found that treadmill exercise for 8 weeks can significantly improve the cognitive dysfunction, alleviate activation of proinflammatory microglia M1 (Iba1 labeling) in the hippocampus of T2DM mice, and reduce the levels of proinflammatory factors IL-1β, IL-6, TNF-α, increase the expression levels of anti-inflammatory factors IL-10, TGF-β1, and promote the release of BDNF. We also found that exercise activate the signaling pathway of SIRT1/ NF-κB and SIRT1/ PGC-1α/ FNDC5/ BDNF. After the application of nicotinamide (NAM, SIRT1 inhibitor), the positive effects of exercise were remarkably suppressed. Our results showed that long-term moderate intensity treadmill exercise can alleviate inflammatory response in the hippocampus and increase BDNF expression in T2DM mice by activating SIRT1.