A series of macrocyclic bisbibenzyls with novel skeletons was designed, synthesized, and evaluated for antiproliferative activity against five anthropic cancer cell lines. Among these novel molecules, compound 47 displayed excellent anticancer activity against HeLa, k562, HCC1428, HT29 and PC-3/Doc cell lines, with IC50 values ranging from of 1.51 μM-5.51 μM, which were more potent than the parent compound, marchantin C. Compounds 44 and 55 with novel bisbibenzyl skeletons also exhibited significantly improved antiproliferative potency. Structure-activity relationship (SAR) analyses of these synthesized compounds were also performed. In addition, compound 47 effectively inhibited tubulin polymerization in HCC1482 cells and induced HCC1482 cell cycle arrest at the G2/M phase in a concentration-dependent manner. The binding mode of compound 47 to tubulin was also investigated utilizing a molecular docking study. In conclusion, the present study discovered several potent antitubulin compounds with novel bisbibenzyl skeletons, and our systematic studies revealed new scaffolds that target tubulin and mitosis and provide progress towards the discovery of novel antitumor drugs discovery.