Objective To elucidate the therapeutic mechanism of Astragalus membranaceus (A. membranaceus) in lung adenocarcinoma (LUAD) through network pharmacology, molecular docking, and in vitro validation. Methods Active components of A. membranaceus were retrieved from the TCMSP, TCMIP databases, and literature, and their potential targets were predicted using SwissTargetPrediction. LUAD-related targets were obtained from GEO, OMIM, DisGeNET, and Genecards database. A protein-protein interaction (PPI) network was constructed using the STRING database. A synergistic network of core components and their co-regulated target clusters was constructed to explore the multi-target regulatory mechanism. GO and KEGG enrichment analyses were performed to identify key biological processes and signaling pathways. Protein expression differences of core targets in LUAD tissues were validated using the Human Protein Atlas (HPA) database. Molecular docking between key targets and major active components was conducted using AutoDock. Finally, the effects of core components on LUAD cell proliferation, migration, apoptosis, and mRNA expression of core target were evaluated using MTT, colony formation, wound healing, flow cytometry, and RT-qPCR assays. Results A total of 44 active components of A. membranaceus (e.g. Quercetin, (R)-Isomucronulatol, Kaempferol) and 58 corresponding potential targets were identified. Core targets include TP53, AKT1, IL6, EGFR, CASP3, TNF, and BCL2. Enrichment analyses suggested that A. membranaceus may exert anti- LUAD effects by modulating biological processes such as oxidative stress, lipopolysaccharides response, response to bacterial-derived molecules and chemical stress response, primarily through the PI3K-AKT, lipid/atherosclerosis, and MAPK signaling pathways. HPA database validation revealed that the protein expression levels of TP53, AKT1, EGFR, CASP3, and BCL2 were upregulated in LUAD tissues. Molecular docking confirmed strong binding affinities between core components and their respective targets. In vitro experiments demonstrated that Quercetin, (R)-Isomucronulatol, and Kaempferol (50 μg/mL) significantly inhibited LUAD cell proliferation and migration, and induced apoptosis (P < 0.05). Furthermore, these compounds upregulated the mRNA expression of tumor suppressor genes (TP53, CASP3, and TNF) and downregulated oncogenes (AKT1, IL6, EGFR, and BCL2) (P < 0.05). Conclusion A. membranaceus exhibits therapeutic potential against LUAD through a multi-target, multi-pathway mechanism, involving key signaling pathways such as PI3K-AKT, lipid/atherosclerosis, and MAPK.