A high-fat diet (HFD) is a common risk factor for Type 2 diabetes mellitus (T2DM) and its associated cognitive impairments. In models of diabetes, resveratrol, a modulator of SIRT1, regulates the fasting glucose and antioxidant levels, as well as the lipid profile. Resveratrol may also alleviate the cognitive dysfunctions associated with diabetes. Albino rats were fed a HFD, (60% kcal fat) after treatment with streptozotocin (45 mg·kg-1 ,i.p., single dose) to induce an experimental model of T2DM. After 14 weeks of the animals in confirmed diabetic condition, they were treated with metformin (200 mg·kg-1 ,i.p.) or resveratrol (50 or 100 mg·kg-1 ,i.p.) for 4weeks. Levels of oxidative-nitroso-stress, SIRT1, TGF-β1, inflammation and cholinergic activity were determined in plasma, hippocampus and cerebral cortex. A battery of behavioural studies associated with learning memory were performed during and after the experimental protocol. Treatment with resveratrol attenuated the increased glucose levels (pre- and post-prandial), impaired glucose tolerance, HbA1c, and decreased the body weights of the T2DM rats. Moreover, resveratrol ameliorated the impaired learning and memory associated with increased SIRT1 and decreased TGF-β1, TNF-α, oxidative-nitroso-stress, and cholinergic activities in the plasma and the brains of the T2DM animals. Our results demonstrated that SIRT1 modulation interacted with TGF-β1 signalling, and mitigated hyperglycaemia and subsequent learning-memory impairments in the T2DM animals. Our study also suggested novel therapeutic targets, including TGF-β1, which may add to our knowledge of resveratrol, when used to treat impaired memory associated with diabetes.