Major Depressive Disorder (MDD) is one of the main causes of suicide. Monoamines, the mainstay of treatment for the disease, have limited efficacy, highlighting the urgent need for improved treatment. Traditional Chinese medicine (TCM) has shown the advantages of multiple mechanisms of action and fewer side effects in this field, which has become a potential treatment option. In recent years, the important regulatory role of GR/NF-κB/NLRP3 signaling pathway in the treatment of depression has gradually attracted attention. Studies have shown that this signaling pathway is mainly closely related to the hypothalamic-pituitary-adrenal axis, the inhibition of neuroinflammation and the regulation of nerve cell pyroptosis. This article reviews the mechanism of traditional Chinese medicine"s antidepressant effect by regulating GR/NF-κB/NLRP3 signaling pathway, in order to provide theoretical basis for the treatment and further research of depression.