Depression is a disorder with a high incidence that has been increasing worldwide although the pathophysiology remains unclear. Moreover, some studies revealed a higher concentration of glutamate and oxidative stress in the patients' brain, which causes cell death by excitotoxicity. Morus nigra L. is known as black mulberry and its leaves are popularly used to treat affections related to menopause, obesity and high cholesterol. M. nigra leaves are a rich fount of phenolics which well-known by the antioxidant property. Herein, we examined the phenolic profile and the antidepressant-like effect of the Morus nigra aqueous extract (MN) and its major phenolic constituent, syringic acid (SA). Furthermore, the involvement of antioxidant and neuroprotective activities were further evaluated. Our results show that acute and subchronic MN or SA administration exerted antidepressant-like property in the behavioral testes in mice. The results suggest that the antidepressant-like effect of MN, at least in part, could be due to the SA influence. Moreover, the observed effect involves the nitro-oxidative system modulation in both the serum and brain of mice. Furthermore, MN or SA was able to contain the glutamate-induced cell death in the hippocampal and cortical slices implicating the neuroprotection activity in the antidepressant-like effect.