Constitutive high expression of Nrf2 (Nuclear factor erythroid 2-related factor 2) is an important contributor of proliferation and chemoresistance in Non-small cell lung cancer (NSCLC). The aim of this present study was to investigate the Nrf2 inhibitory effect of Trigonelline, its mechanism of action and its possible use in combinatorial treatment with anti- lung cancer drugs, Cisplatin and Etoposide. Our immunofluorescence, western blot and real time PCR data showed that Trigonelline prevented nuclear accumulation of pNrf2 (four folds) and downregulated Nrf2 targeted genes in both A549 and NCIH460 cells. Trigonelline inhibited Nrf2 via reduced activation of EGFR signalling pathway and its downstream effector ERK 1/2 kinase. Trigonelline in combination with Cisplatin/Etoposide abrogated proliferation of NSCLC cells (A549, NCIH460 and NCIH1299) without showing any visible cytotoxicity to the normal lung epithelial cell (L132). Combinatorial treatment of Trigonelline with Cisplatin/Etoposide showed strong synergism at a sufficiently low concentration than the IC50 values of these drugs. Nrf2 knockdown experiment in NSCLC cells obliterated the effect of Trigonelline- Cisplatin and Trigonelline-Etoposide combination, indicating the role of Nrf2 inhibition in augmenting drug sensitivity. Our study demonstrated that Trigonelline blocks Nrf2 activation and its nuclear translocation via inhibition of EGFR signalling pathway. It has improved responsiveness of NSCLC cells for Cisplatin and Etoposide and could be a promising choice for lung cancer therapy. © 2020