Lung squamous cell carcinoma (LSCC) is a common type of non-small-cell lung cancer (NSCLC) and lacks effective treatment. Regorafenib, an oral multikinase inhibitor, has demonstrated promising anti-tumor activity in various solid tumors. To study whether regorafenib inhibits LSCC cells, we investigate the compound in several LSCC cell lines and explore the possible mechanism. In this study, we confirmed that regorafenib had anti-proliferation effect on LSCC cell lines by inducing G0/G1 arrest. In addition, glycogen synthase kinase 3β (GSK3β) remained at the same level and Ser9 phosphorylation of GSK3β decreased with increasing incubation time and increasing regorafenib concentration in LSCC cells. GSK3β inhibition enhanced the anti-tumor activity of regorafenib. Thus, GSK3β activation restricted the anti-cancer effect of regorafenib on LSCC. In conclusion, regorafenib might be a promising drug for LSCC therapy. GSK3β might be a potential target to increase the anti-tumor effect of regorafenib in LSCC cells.