Based on Sorafenib as the lead compound, a series of quinoline derivatives were designed and synthesized as novel Raf kinase inhibitors to improve antitumor activity and optimize Raf kinase activity. The antiproliferative activities of these derivatives against human cancer cell lines HepG2, A549, and KCC-853 were evaluated using the MTT assay with Sorafenib as a reference. Most compounds exhibited better or similar antiproliferative activities compared to Sorafenib, and compound 10f showed superior activity with IC50 values of 6.356, 0.916, and 1.102 μM against HepG2, A549, and KCC-853, respectively (vs. Sorafenib's 12.669, 5.231, and 6.779 μM). Further, the Raf kinase inhibitory activities of the compounds were tested, and compound 10f demonstrated more potent inhibition (8.7 nM) than Sorafenib (28.5 nM). Structure-activity relationship (SAR) studies were conducted by introducing diverse substituents (electron-withdrawing groups like fluoro and electron-donating groups like methyl) on the phenyl ring connected to the urea moiety, and compounds with para-fluoro groups exhibited reasonable antitumor activities. These quinoline derivatives are promising Raf kinase inhibitors, and compound 10f is a potent and selective candidate.