Objective: Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. Methods: PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: “amantadine AND depress*”; “amantadine AND mood”; “amantadine AND animal models AND antidepres*”; and “amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference).” Results: Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. Conclusion: Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.