Though Fisetin was known to exhibit antitumor effect in prostate, colon, breast, stomach, and lung cancers, the underlying antitumor mechanism is not fully understood in non-small cell lung cancers (NSCLCs).Thus, the aim of the present work is to elucidate the antitumor mechanism of Fisetin in A549 and H460 NSCLC cells in association with ribosomal biogenesis and ubiquitin ligase proteins.Fisetin showed cytotoxic and antiproliferative effects in a concentration and time dependent manner in A549 and H460 cells.Also, Fisetin increased the number of Annexin V/PI positive apoptotic portion and sub G1 accumulation in A549 and H460 cells.Additionally, Fisetin cleaved Poly ADP-ribose polymerase (PARP) and caspase 3 and increased p53, attenuated the expression of G1 phase related proteins such as cyclin D1, cyclin E and CDK2 and ribosomal biogenesis related gene Exportin 1 (XPO1) in A549 and H460 cells.Of note, Fisetin abrogated the expression of driver oncogenses such as c-Myc, S-Phase Kinase Associated Protein 2 (SKP2) and Cullin 4A (CUL4A) in A549 and H460 cells.Conversely, depletion of XPO1 enhanced p53 and PARP cleavage, while depletion of CUL4A promoted PARP cleavage without p53 upregulation in H460 cells.Overall, these findings highlight evidence that XPO1 mediated c-Myc and CUL4A signaling is critically involved in Fisetin induced apoptotic effect in NSCLCs as a potent antitumor candidate