Background: Depression is a severe, chronic, and recurring mental health disorder, which prevalence and morbimortality have increased in recent years. Several theories are proposed to elucidate the mechanisms of depression, such as the involvement of inflammation and the release of cytokines. Alternative treatments have been developed to improve outcomes of the commonly used drugs, and the use of Curcuma longa stands out. Its primary compound is named curcumin that exhibits antioxidant and anti-inflammatory effects. Aims: Several studies have shown that curcumin may play antidepressant actions and, therefore, this study aimed to perform a systematic review of the antidepressant effects of curcumin to evaluate the impact of this compound in the treatment of this condition. Methods: This systematic review has included studies available in MEDLINE–PubMed, EMBASE, and Cochrane databases, and the final selection included 10 randomized clinical trials. Conclusion: Curcumin improves depressant and anxiety behavior in humans. It can increase monoamines and brain-derived neurotrophic factor levels and may inhibit the production of pro-inflammatory cytokines and neuronal apoptosis in the brain. Systemically, curcumin enhanced insulin sensitivity, reduced cortisol levels, and reversed metabolic abnormalities. Studies with larger samples and standardized dose and formulation are required to demonstrate the benefits of curcumin in depression treatment since there are many variations in this compound’s use.