In both A549 and NCIH460 cells, trigonelline (50 μM) reduced nuclear accumulation of pNrf2 by fourfold and downregulated Nrf2 targeted genes. Trigonelline inhibited Nrf2 by reducing EGFR signaling pathway activation and its downstream effector ERK 1/2 kinase. Trigonelline in combination with Cisplatin/Etoposide inhibited NSCLC cell proliferation (A549, NCIH460, and NCIH1299) without causing cytotoxicity in normal lung epithelial cells (L132). This evidence concerns the gene EGFR and non-small cell lung carcinoma.