Major depressive disorder is a mental disorder characterized by persistent low mood, loss of interest, loss of appetite, and sleep disorders. At present, monoamines are the main drugs for the treatment of this disease; however, the clinical application of these drugs is limited. The multi-target, multi-link, and holistic regulation of traditional Chinese medicine (TCM) makes it a promising treatment option. In recent years, the role of the GR/ NF-κB/ NLRP3 signaling pathway in the pathogenesis and treatment of depression has attracted attention.Studies have shown that this signaling pathway is closely related to the hypothalamic-pituitary-adrenal axis, the inhibition of neuroinflammation, and the regulation of nerve cell pyroptosis. This article reviews the mechanism underlying the antidepressant effect of TCM via the regulation of the GR/ NF-κB/ NLRP3 signaling pathway, providing a theoretical basis for treatment and further research on depression.