Depression is a common clinical psychological disease, which is called "yu zheng" in traditional Chinese medicine (TCM). TCM has a long history in the treatment of depression (yu zheng), which has unique advantages. Jieyu pill (JYP), a classical TCM formula, has been widely used for treating depression because of its clear clinical efficacy, low side effects, and high compliance. In this review, we systematically introduce recent clinical and animal experimental studies on JYP and depression, and review the pharmacological mechanism and active ingredients of JYP, as well as its clinical application in depression therapy. This systematic review provides a deep understanding of TCM prescriptions, pharmacological mechanisms, and disease-medicine interactions, and lays the foundation for developing new treatments for depression.