Oroxin A (OA), a bioactive compound derived from Oroxylum indicum (L.) Kurz, exhibits significant therapeutic potential against malignant tumors. OA's anti-NSCLC (non-small cell lung cancer) mechanism was explored using an integrated methodology encompassing both bioinformatic predictions and experimental confirmations. Publicly available databases were utilized to retrieve targets related to OA and NSCLC. Common targets between OA and NSCLC were identified through Venny analysis. The protein-protein interaction (PPI) network was constructed employing the STRING database. Functional annotation was carried out via the DAVID database. Additionally, binding affinities were assessed using molecular docking, followed by the molecular dynamics simulation conducted in Gromacs v2022.03. Evaluation of protein expression differences between NSCLC and normal lung tissues was performed via the HPA database. Based on network pharmacology, cell counting kit-8 (CCK-8), wound healing, western blot, and apoptosis assays were conducted to verify the inhibitory effect of OA on A549 and LLC cells. OA yielded 186 potential targets, while NSCLC yielded 600 targets, revealing 42 shared candidates. The PPI network identified EGFR, HSP90AA1, SRC, TNF, and AKT1 as the key proteins. From the bioenrichment results, 117 distinct signaling pathways emerged, notably featuring the PI3K-AKT signaling pathway. Molecular docking revealed that OA binds tightly to EGFR, HSP90AA1, SRC, TNF, and AKT1. The molecular dynamics simulation confirmed that OA binds firmly to EGFR. Immunohistochemical analysis revealed significantly elevated expression levels of key targets, including EGFR, in NSCLC tissues compared to normal controls. In vitro experiments revealed that OA significantly suppressed cell migration in A549 and LLC lines while inducing apoptosis, potentially through inhibition of the HSP90AA1/AKT pathway.© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.