Twenty-three resveratrol derivatives possessing chalcone moiety were synthesized and characterized, and their biological activities were also evaluated as potential antiproliferation and tubulin polymerization inhibitors. Compound C19 exhibited the most potent activity in vitro, which inhibited the growth of HepG2, B16-F10, and A549 cell lines with IC(50) values of 0.2, 0.1, and 1.4 μg/mL, respectively. Compound C19 also exhibited significant tubulin polymerization inhibitory activity (IC(50)=2.6 μg/mL). Docking simulation was performed to position compound C19 into the tubulin-colchicine binding site to determine the probable binding mode.