Diabetic cardiomyopathy (DCM) is a serious complication of diabetes with limited therapeutic options. This study investigated the potential synergistic cardioprotective effects of combining agomelatine (AGM), a melatonergic agonist, with empagliflozin (EMPA), an SGLT2 inhibitor, in a mouse model of DCM. Diabetes was induced in mice using streptozotocin. Animals were treated with AGM (20 mg/kg/day), EMPA (20 mg/kg/day), a low-dose combination of AGM and EMPA (10 mg/kg/day each), or vehicle for 6 weeks. Cardiac function, biochemical markers, histopathology, and protein expression related to oxidative stress, inflammation, fibrosis, and apoptosis were assessed. The low-dose combination of AGM and EMPA significantly attenuated hyperglycemia (reducing plasma glucose levels from approximately 20 mM-10 mM), improved cardiac function, and reduced myocardial injury and hypertrophy compared to monotherapy. Histopathological analysis revealed reduced cardiac fibrosis, inflammation, and myocyte damage in the combination group. Furthermore, the combination therapy synergistically enhanced endogenous antioxidant capacity by increasing Nrf2 and HO-1 expression and SOD activity, while decreasing MDA levels. It also effectively suppressed myocardial inflammation, fibrosis, and apoptosis, as evidenced by reduced NF-κB, TGF-β, and caspase-3 expression. These findings demonstrate the synergistic cardioprotective effects of combining AGM and EMPA in DCM, suggesting that this low-dose combination therapy may offer a promising new therapeutic strategy for managing this challenging condition.