Depression, a neurological disorder, is a universally common and debilitating illness where social and economic issues could also become one of its etiologic factors. From a global perspective, it is the fourth leading cause of long-term disability in human beings. For centuries, natural products have proven their true potential to combat various diseases and disorders, including depression and its associated ailments. Translational informatics applies informatics models at molecular, imaging, individual, and population levels to promote the translation of basic research to clinical applications. The present review summarizes natural-antidepressant-based translational informatics studies and addresses challenges and opportunities for future research in the field.