Resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is frequently driven by MET amplification. We evaluated isoalantolactone (IAL), a plant-derived sesquiterpene lactone, in EGFR-mutant HCC827 cells and gefitinib-resistant, MET-amplified HCC827GR cells. Anticancer activity was assessed using viability and anchorage-independent growth assays, in vitro kinase assays, molecular docking, Western blotting, and flow cytometry–based analyses of reactive oxygen species (ROS), cell cycle, and apoptosis. IAL reduced viability and colony growth in both parental and resistant cells while showing low toxicity in normal cells. In vitro kinase assays and docking suggested direct dual targeting of EGFR and MET, and Western blotting confirmed reduced phosphorylation of EGFR, MET, and downstream AKT. IAL induced G2/M arrest, accompanied by p27 upregulation and cyclin B1/Cdc2 downregulation. IAL also increased intracellular ROS and increased annexin V–positive cell populations; N-Acetyl-L-cysteine restored viability and attenuated caspase activation. Notably, the pan-caspase inhibitor Z-VAD-FMK significantly rescued viability, confirming caspase-dependent apoptosis. Collectively, IAL shows potent anticancer effects in EGFR-mutant and gefitinib-resistant NSCLC through dual EGFR/MET inhibition and ROS-driven, caspase-mediated apoptosis, supporting IAL as a candidate to overcome EGFR-TKI resistance.