Rationale <p>Depression is a common mood disorder that seriously affects the quality of life and working ability of patients. Zhi-Zi-Hou-Po Decoction (ZZHPD), a classical formula from the Traditional Chinese Medicine (TCM), is widely used to treat depression. Although ZZHPD exhibits potent antidepressant effects, its specific mechanism of action and active ingredients remain unknown.</p> Objectives <p>This article focused on identifying and analysing the major phytochemical in ZZHPD that exhibit antidepressant effects. It also provided theoretical data for the standardized clinical application of ZZHPD.</p> Methods <p>A systematic review of the materia medica, chemical composition, and pharmacological effects from multi-source literature databases to elucidate the antidepressant mechanism of ZZHPD. And further validation was performed using a comprehensive bioinformatics analysis of network pharmacology and molecular docking.</p> Results <p>The antidepressant effect of ZZHPD is achieved through multiple pathways and targets. The key phytochemical constituents of ZZHPD include 3 categories, iridoids, flavonoids, and lignans, which are specifically included geniposide, magnolol, honokiol, hesperidin, hesperetin, naringin, naringenin, nobiletin, and 3,5,6,7,8,3’,4’-heptamethphoxyflavone (HMF). The main antidepressant mechanisms include enhancing monoaminergic system function, inhibiting neuroinflammation, restoring HPA axis negative feedback, enabling neurogenesis and neuroplasticity, neuroprotective effects, inhibition of neuronal apoptosis and pyroptosis, antioxidative stress, and regulation of noncoding RNA.</p> Conclusions <p>In summary, ZZHPD demonstrates antidepressant effects through multi-component, multi-target, and multi-pathway mechanisms. It shows promise for treating depression at the molecular, cellular, and systemic levels, with significant clinical application value.</p>