Objective：To investigate the ameliorating effect of catalpa alcohol-paeoniflorin (CTP-PNF) on perimenopausal depression (PMD) and its potential mechanism by inhibiting miR-124 to promote the proliferation and migration of neural stem cells. Methods : The intervention effect of CTP-PNF was systematically evaluated by establishing a human-derived PMD mouse model, using brain-localized microinjection of miR-124 inhibitor/control, and in vitro fetal mouse neural stem cell extraction and transfection experiments. Sucrose preference test (SPT), tail suspension test (TST) and new environment food suppression test (NSFT) were used to detect depressive-like behaviors in mice. qRT-PCR was used to detect the expression of miR-124 in mouse prefrontal cortical tissues. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and γ-aminobutyric acid (GABA) in serum and prefrontal cortex. Nissl staining was used to detect the pathological status of neurons in the prefrontal cortex and hippocampus. MTT was used to detect cell viability. Transwell assay to test migration capability; Network pharmacology was used to comprehensively analyze the common targets of miR-124-mediated CTP-PNF intervention in PMD, and the protein-protein interaction network was established, and the David platform was used for gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Results: The results showed that compared with the model group, CTP-PNF could significantly improve the depressive-like behavior and reduce the expression of miR-124 in the prefrontal cortex (P<0.001). Inhibition of miR-124 expression reduced depression-like behavior, increased the content of neurotransmitters (P<0.05), and improved nerve damage in the prefrontal cortex and hippocampus. The intervention of CTP-PNF medicated serum and the silencing of miR-124 can improve the vitality of neural stem cells, enhance their migration ability, and promote neural stem cell repair. Comprehensive bioinformatics analysis of network pharmacology showed that miR-124-mediated CTP-PNF treatment of PMD mainly involved 56 core therapeutic targets, and its key pathways included "hypoxia-inducible factor 1 signaling pathway", "serotonergic synaptic signaling pathway" and "cAMP signaling pathway" related to MAPK1, STAT3, TP53 and VEGFA. Conclusions: This study confirms that CTP-PNF significantly ameliorates depressive-like behaviors and neuropathological damage in perimenopausal depression mice by downregulating miR-124 to promote neural stem cell proliferation/migration and regulate neurotransmitter networks. Its effects involve multiple signaling pathways including hypoxia-inducible factor 1 and serotonergic synapse, providing a novel TCM intervention strategy and molecular targets for treating perimenopausal depression.