BACKGROUND: High fat consumption is a known risk factor for the development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been found to possess anti-inflammatory and neuroprotective properties. However, the cognitive effects and mechanisms of SGLT2is on female mice fed with a high-fat diet remain unknown. OBJECTIVE: This study aimed to investigate the impacts of dapagliflozin on metabolism, cognition, neuroinflammation, insulin resistance, and microglial activation in female mice fed a HFD. METHODS: Dapagliflozin (1 mg/kg) was administered to HFD-fed mice for 24 weeks. Body weight, glucose tolerance, and insulin resistance were assessed. Additionally, all mice were subjected to the Morris water maze (MWM) and one-trial Y-maze tests. The levels of metabolic hormones and cytokines were analyzed using ELISA kits. The levels of phosphorylated tau (p-tau) protein in the hippocampus were measured. Microglia, insulin receptors, NLRP3, and IL-1β in the hippocampus of mice were evaluated by immunofluorescence or immunohistochemical staining. RESULTS: As anticipated, dapagliflozin improved insulin resistance and glucose metabolism and reduced cognitive impairment in female mice fed with a HFD. In the hippocampus, dapagliflozin alleviated microglial activation yet did not reduce the secretion of inflammatory chemokines. Furthermore, it increased the expression of insulin receptor in the hippocampus of HFD-fed mice and decreased the expression of p-tau. CONCLUSIONS: Our results provide a foundation for the clinical application of SGLT2is as an adjuvant to slow down the progression of central degenerative diseases related to metabolic disorders, such as AD.