Overcoming therapeutic resistance remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated the anticancer activity of cynaropicrin (Cyn), an artichoke-derived sesquiterpene, in NSCLC cell lines with distinct genetic characteristics and different responses to gefitinib (GEF). Cell viability and soft-agar colony formation assays showed that Cyn preferentially suppressed the growth and clonogenic survival of NSCLC cells, including GEF-resistant HCC827GR cells. Western blot analysis revealed that Cyn reduced the phosphorylation levels of EGFR, MET, and AKT. Consistently, in vitro kinase assays, ATP competition assay, and molecular docking analyses supported the inhibitory effects of Cyn on EGFR and MET kinase activity. Flow cytometric analysis using propidium iodide staining, along with western blotting of cell cycle-related proteins, demonstrated that Cyn induced cell cycle arrest by altering the expression of key cell cycle regulators. In addition, Cyn enhanced reactive oxygen species (ROS) generation, lipid peroxidation, and caspase activation, ultimately promoting both apoptotic and ferroptotic cell death in NSCLC cells. Cyn exerted anticancer effects in NSCLC cells regardless of their sensitivity or resistance to GEF. Further investigation is warranted to determine the therapeutic applicability of Cyn in NSCLC harboring various mechanisms of drug resistance.