Background: Diabetic individuals have a higher incidence of depression compared to the general population, and it is a significant risk factor for cardiovascular complications in those patients. In turn, depression and type 2 diabetes mellitus (T2DM), as well as its macrovascular complications, have a reciprocal relationship. Agomelatine, an atypical antidepressant, has been shown to have anti-inflammatory and antioxidant activities. It is a melatonin receptor agonist and a serotonin receptor antagonist. Objective: To demonstrate the protective effects of agomelatine on cardiovascular and hyperglycemic disorders. Methodology eighteen adult male albino rats were included in the study and assigned into three groups: Group I: Considered as control group, Group IIa: Diabetic (non-treated) group where diabetes was induced by 20%weight/volume (W/V) fructose sweetened water for 14 days followed by intraperitoneal injection of alloxan at a dosage of 150 mg/kg, Group IIb: Diabetic agomelatine treated group; received agomelatine (20 mg/kg/day) for four consecutive weeks. Blood pressure and electrocardiogram (ECG) measurements were performed. Blood samples were collected for measuring of tumor necrosis factor-alpha level, blood glucose level, glycated hemoglobin, and serum insulin in the end of experimental period.  Additionally, the histopathological examination for aortic and heart tissues was performed. Results: Agomelatine produced a significant (p< 0.001) decreased systolic, diastolic and mean arterial blood pressure and improved ECG abnormalities. The same treatment caused a significant (P<0.001) decrease in tumor necrosis factor-alpha (TNF-α) level, blood glucose level, glycated hemoglobin, and improvement of insulin resistance, in addition to a significant increase in serum insulin level. Histopathological changes in myocardial and aortic tissues were also improved by agomelatine. Conclusion: Agomelatine has a cardio-protective effect against cardiovascular abnormalities in the diabetic rats that may be mediated by improvement of glucose hemostasis, restoration of hemodynamics (blood pressure and ECG), increased nitric oxide (NO) bioavailability, and alleviation of inflammation.