Obese-insulin resistance can lead to the impairment of brain mitochondrial function, brain insulin receptor function, hippocampal synaptic plasticity as well as cognition. The dipeptidyl peptidase-4 inhibitor (DPP4-i) vildagliptin has been shown to attenuate these impairments in the brain. Recently, sodium glucose co-transport 2 inhibitor (SGLT2-i), a new class of antidiabetic drugs, had been shown to exert neuroprotection and prevent cognitive decline in a diabetic mice model. Despite these reports, the comparative effects of the DPP4-i and the SGLT2-i and the combined drugs therapy on the cognitive function impaired by the obese-insulin resistant condition have never been investigated. We hypothesized that the SGLT2-i (dapagliflozin) and the combined drugs exert better efficacy than DPP4-i (vildagliptin) on improving metabolic parameters and brain function in obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to receive either normal diet (ND) (n=6) or high-fat diet (HFD) (n=24) for 16 weeks. At week 13, HFD-fed rats were subdivided into 4 subgroups (n=6/subgroup) to receive either vehicle (0.9%NSS, 0.1 mg/kg/day; intragastric gavage), vildagliptin (3mg/kg/day; intragastric gavage), dapagliflozin (1 mg/kg/day; intragastric gavage) and the combined vildagliptin and dapagliflozin for 4 weeks. ND-fed rats were given vehicle for 4 weeks. At the end of the treatment, cognitive function, metabolic parameters, brain mitochondrial function, brain insulin sensitivity, and hippocampal synaptic plasticity were determined. HFD-fed rats treated with vehicle developed peripheral insulin resistance and cognitive decline with impaired hippocampal synaptic plasticity, brain mitochondrial dysfunction, and brain insulin resistance. Dapagliflozin therapy exerted better efficacy on improved peripheral insulin sensitivity and reduced body weight gain, when compared to vildagliptin. In the brain, either dapagliflozin or vildagliptin equally improved brain mitochondrial function, brain insulin sensitivity and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. Surprisingly, combined drugs exerted greater efficacy in increased brain insulin sensitivity than monotherapy. All findings were concluded in table 1. Both vildagliptin and dapaglifozin share similar efficacy on improving brain mitochondrial function, brain insulin sensitivity and preventing cognitive decline in obese-insulin resistant rats. However, dapaglifozin exert better efficacy on the improvement of metabolic profiles and hippocampal synaptic plasticity than vildagliptin.