Major depressive disorder (MDD) is a common psychiatric disorder characterized by significant mood disturbances and cognitive impairments. Chronic stress, particularly social defeat stress, plays a crucial role in the etiology of depression, with oxidative stress being a pivotal factor in its pathophysiology. Consequently, identifying effective strategies to mitigate oxidative stress and prevent the progression of depression is of paramount importance. Agomelatine, an atypical antidepressant with melatonergic and serotonergic properties, has shown promise in treating MDD due to its unique mechanisms of action. In this study, we aimed to investigate whether agomelatine could ameliorate behavioral deficits in a chronic social defeat stress (CSDS) mouse model. CSDS mice were administered agomelatine (50 mg/kg, intraperitoneally) and exhibited significant reductions in both anxiety-like and depressive-like behaviors in behavioral tests. Further analysis revealed that agomelatine treatment effectively reduced oxidative damage in the hippocampus of CSDS mice. Additionally, agomelatine attenuated mitochondrial dysfunction and restored synaptic plasticity, as evidenced by an increased density of excitatory synapses and enhanced neuronal activity. These findings suggest that agomelatine may exert therapeutic effects by reducing oxidative stress, preserving mitochondrial function, and enhancing synaptic plasticity, providing new insights into its potential as a treatment for chronic social defeat stress-induced depression.