Abstract: Objective: To explore the potential therapeutic targets and mechanisms of resveratrol in the treatment of non-small cell lung cancer (NSCLC), a comprehensive study was conducted incorporating network pharmacology, molecular docking methods, and experimental validation. Methods: The targets of resveratrol were searched on Swiss Target Prediction database and Target net database. NSCLC targets were gathered from Genecards, OMIM, TTD databases. The intersection of drug targets and disease targets was obtained using Venny 2.1.0 platform. Next, Cytoscape 3.7.2 software was applied along with the String database to generate target protein interaction networks (PPI) and perform topological analysis. GO functional enrichment analysis and KEGG pathway enrichment analysis of intersecting targets were conducted using the Metascape database, resulting in gene maps of the intersecting targets. Molecular docking studies were performed for the top three ranked core targets and resveratrol using Autodock Vina software. Clinical case samples were obtained from The Cancer Genome Atlas (TCGA) database to analyze the expression of relevant targets in NSCLC patients (n=1017) and healthy controls (n=627). The effects of different concentrations (30 and 50 μmol/L) of resveratrol on the protein expression of SRC, EGFR and PI3K/AKT signaling pathway in human lung adenocarcinoma A549 cells were examined using Western Blot at the cellular level. Results: Total of 40 potential targets were screened out, followed by obtaining 8 key targets after topological analysis. These keys targets, including EGFR, SRC, and ESR1 were closely associated with NSCLC. The treatment of NSCLC with resveratrol primarily involved multiple signaling pathways, such as tumor proteoglycans, estrogen signaling and PI3K/AKT. Molecular docking results demonstrated that resveratrol had a good binding ability with the target protein. Clinical sample results revealed that the expression of EGFR, SRC, ESR1, HSP90AA1, and MMP9 was upregulated, while the expression of TNF, CDC42, and RELA was downregulated in NSCLC patients. Cellular experiments indicated that resveratrol could inhibit the protein expression of SRC, EGFR, p-PI3K, and p-AKT in human lung adenocarcinoma A549 cells in a dose-dependent manner. Conclusion: This study demonstrates that resveratrol involves multiple targets and signaling pathways in the treatment of NSCLC, and clarifies that resveratrol could exert its anti-cancer effects by inhibiting the PI3K/AKT signaling pathway.