Brexpiprazole, a novel atypical antipsychotic agent, has recently been approved as an adjunctive treatment for major depressive disorder (MDD) when monotherapy only provides a partial response. The mechanism of action is likely related to its partial agonist activity at D2 and 5-HT1A receptors, as well as potent 5-HT2A antagonist effects. The purpose of this systematic review is to provide a detailed overview available evidence on its role in treating MDD, based on all clinical publications in the English language between January 1, 2014 and April 30, 2017 identified from PubMed, Google Scholar, Scopus, Web of Science, PsycINFO, and ClinicalTrials.gov. Two primary pivotal trials are reviewed in detail and a further 10 supporting reviews and open-label studies are discussed. Brexpiprazole is compared with aripiprazole according to pharmacologic and clinical activities. Overall, this appears to be a useful antidepressant adjunctive therapy with a favorable side effect profile and comparable efficacy with existing agents.