In this studies, we demonstrated that regorafenib can induce both death receptor dependent apoptosis (extrinsic) and mitochondria dependent apoptosis (intrinsic) signaling. On the other side, regorafenib successfully suppressed AKT/NF-κBmediated tumor progression ability. Through the inactivation of AKT/NF-κBsignaling by regorafenib, tumor angiogenesis (VEGF), proliferation (CyclinD1) and anti-apoptosis (C-FLIP, MCL-1, XIAP, survivin) effect were all markedly diminished. Display omitted •Regorafenib induced apoptosis through extrinsic/intrinsic pathways in NSCLC cells and animal.•Regorafenib reduced NSCLC cells invasion capacity.•Regorafenib suppressed inhibited NSCLC tumor growth.•Regorafenib inhibited tumor progression was associated with blockage of AKT/NF-κB signaling. Non-small cell lung cancer (NSCLC) is a malignant lung cancer type with poor prognosis. NF-κB, the oncogenic transcription factor, has been recognized as an important mediator in progression of NSCLC. Regorafenib, a multikinase inhibitor, was demonstrated to inhibit tumor progression through suppression of ERK/NF-κB signaling in hepatocellular carcinoma cells in vitro and in vivo. However, whether regorafenib inhibit progression of NSCLC is ambiguous. Thus, the major purpose of present study was to evaluate anticancer efficacy and underlying mechanism of regorafenib on tumor progression in NSCLC in vitro and in vivo. CL-1-5-F4 cells were treated with regorafenib, NF-κB (QNZ) or AKT (LY294002) inhibitor for 24 or 48 h. Then, we performed cell viability assay, NF-κB reporter gene assay, transwell invasion assay and apoptosis related flow cytometry assay on cellular level to verify anti-cancer effect and mechanism of regorafenib. CL-1-5-F4 bearing animal model was treated with vehicle or regorafenib for 28 days. The therapeutic efficacy and mechanism of regorafenib in CL-1-5-F4 bearing animal model were investigated by tumor size evaluation, whole body computer tomography (CT) scan, Haemotoxylin and Eosin (H&E) stain and immunohistochemistry (IHC) stain. Our results demonstrated regorafenib significantly inhibited tumor growth and induced apoptosis through extrinsic/intrinsic pathways in NSCLC in vitro and in vivo. Furthermore, we also found the suppression of AKT/NF-κB signaling was required for regorafenib inhibited expression of progression-related and invasion-related proteins. Our finding indicated apoptosis induction and suppression of AKT/NF-κB signaling were associated with regorafenib-inhibited progression of NSCLC in vitro and in vivo.