The tumor microenvironment (TME) is a decisive determinant of therapeutic response and the emergence of drug resistance in lung cancer. Among its stromal constituents, mesenchymal stem cells (MSCs) are pivotal regulators of disease progression because they secrete diverse paracrine mediators. Accumulating evidence indicates that MSC-derived cytokines, growth factors, and extracellular vesicles (EVs) drive epithelial-mesenchymal transition (EMT)-a phenotypic shift that augments cellular motility, invasiveness, and stem-like traits. EMT contributes directly to resistance against epidermal growth factor receptor tyrosine kinase inhibitors and platinum-based chemotherapy. Key MSC-secreted factors, such as TGF-β1, interleukin-6, and C-C motif chemokine ligand 5, activate signal transducer and activator of transcription 3, phosphoinositide 3-kinase/AKT, and Wnt/β-catenin cascades, thereby reinforcing drug-resistant phenotypes. MSC-induced EMT also remodels immune surveillance and supports the persistence of residual tumor clones. Elucidating the molecular reciprocity between MSCs and lung cancer cells within the TME is indispensable for rational therapy design. This review synthesizes current mechanistic insights into MSC-mediated EMT-driven resistance and discusses translational strategies including targeted inhibition of paracrine signaling and EV engineering that may restore drug sensitivity in lung cancer.