Objective: To identify core acupoint patterns and elucidate the molecular mechanisms of acupuncture for primary depressive disorder (PDD) through data mining and network analysis. Methods: A comprehensive literature search was conducted across PubMed, Embase, Ovid Technologies (OVID), Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), China National Knowledge Infrastructure Database (VIP), Wanfang Data, and SinoMed Database from database foundation to January 31, 2025, for clinical studies on acupuncture treatment of PDD. Descriptive statistics, high-frequency acupoint analysis, degree and betweenness centrality evaluation, and core acupoint prescription mining identified predominant therapeutic combinations for PDD. Network acupuncture was used to predict therapeutic target for the core acupoint prescription. Subsequent protein-protein interaction (PPI) network and molecular complex detection (MCODE) analyses were conducted to identify the key targets and functional modules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses explored the underlying biological mechanisms of the core acupoint prescription in treating PDD. Results: A total of 57 acupoint prescriptions underwent systematic analysis. The core therapeutic combinations comprised Baihui (GV20), Yintang (GV29), Neiguan (PC6), Hegu (LI4), and Shenmen (HT7). Network acupuncture analysis identified 88 potential therapeutic targets (79 overlapping with PDD), while PPI network analysis revealed central regulatory nodes, including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, toll-like receptor 4 (TLR4), IL-10, brain-derived neurotrophic factor (BDNF), transforming growth factor (TGF)-β1, C-X-C motif chemokine ligand 10 (CXCL10), mitogen-activated protein kinase 3 (MAPK3), and nitric oxide synthase 1 (NOS1). MCODE-based modular analysis further elucidated three functionally coherent clusters: inflammation-homeostasis (score = 6.571), plasticity-neurotransmission (score = 3.143), and oxidative stress (score = 3.000). GO and KEGG analyses demonstrated significant enrichment of the MAPK, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and hypoxia-inducible factor (HIF)-1 signaling pathways. These mechanistic insights suggested that the antidepressant effects mediated through mechanisms of neuroinflammatory regulation, neuroplasticity restoration, and immune-oxidative stress homeostasis. Conclusion This study reveals that acupuncture alleviates depression through a multi-level mechanism, primarily involving the neuroinflammation suppression, neuroplasticity enhancement, and oxidative stress regulation. These findings systematically clarify the underlying mechanisms of acupuncture’s antidepressant effects and identify novel therapeutic targets for further mechanistic research.