Background/Aim: The combination of regorafenib with cisplatin/pemetrexed has indicated controllable safety and encouraging antitumor activity in non-small cell lung cancer (NSCLC) patients. However, the anti-NSCLC effects and action mechanisms of regorafenib combined with cisplatin is ambiguous. The major goal of the study was to study the inhibitory effects and action mechanisms of regorafenib combined with cisplatin in NSCLC cells. Materials and Methods: Cell viability, flow cytometry, immunofluorescence staining, western blotting, migration, and invasion assays were employed to verify the anti-NSCLC effects and mechanisms of regorafenib in combination with cisplatin. Results: Cisplatin-induced epidermal growth factor receptor (EGFR)/nuclear factor ĸB (NF-ĸB) signaling was effectively inhibited by regorafenib treatment. Regorafenib, erlotinib (EGFR inhibitor) and QNZ (NF-ĸB inhibitor) may all enhance the cytotoxicity effect of cisplatin. The invasion ability was effectively decreased by combination treatment. Caspase-dependent and -independent apoptosis was activated by cisplatin combined with regorafenib. Conclusion: Apoptosis induction and EGFR/NF-ĸB inactivation correlate with regorafenib-enhanced anti-NSCLC efficacy of cisplatin.This study provides evidence of the therapeutic efficacy of regorafenib in combination with cisplatin on NSCLC.Cisplatin, a platinum-based anticancer drug, is standard treatment for advanced non-small cell lung cancer (NSCLC). DNA damage-induced apoptosis correlates with the anticancer mechanism of cisplatin (1, 2). Cell and animal models have revealed that enhancement of apoptosis induction and suppression of oncogenic signaling such as Wnt, AKT, epidermal growth factor receptor (EGFR), and nuclear factor-kappaB (NF-ĸB) by potential complementary approaches have been reported to sensitize NSCLC cells to cisplatin (3-6). For instance, sodium valproate, a histone deacetylase inhibitor, and microRNA miR-381 have been found to enhance anti-NSCLC efficacy of cisplatin through inducing apoptosis and inhibiting NF-ĸB signaling, respectively (7, 8).Several tyrosine kinase inhibitors (TKIs) targeting EGFR and anaplastic lymphoma kinase (ALK) have been shown to improve survival of NSCLC patients receiving platinum-based doublet chemotherapy (9, 10). Regorafenib, an oral multitarget TKI, is used for the treatment of solid tumors such as hepatocellular carcinoma (HCC), renal cell carcinoma, differentiated thyroid cancer, and metastatic colorectal cancer (11,12). Induction of apoptosis and down-regulation of AKT/NF-ĸB signaling were associated with regorafenibinhibited progression of NSCLC cells (13). In addition, the combination of regorafenib with cisplatin/pemetrexed has shown manageable tolerability and encouraging antitumor 2569 This article is freely accessible online.