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A series of novel indole‐1,2,4‐triazole derivatives have been designed, synthesized, and evaluated as potential tubulin polymerization inhibitors. The top hit 12, bearing the 3,4,5‐trimethoxyphenyl moiety, exhibited substantial anti‐proliferative activity against HepG2, HeLa, MCF‐7, and A549 cells in vitro with IC50 values of 0.23 ± 0.08 μM, 0.15 ± 0.18 μM, 0.38 ± 0.12 μM, and 0.30 ± 0.13 μM, respectively. It also inhibited tubulin polymerization with the IC50 value of 2.1 ± 0.12 μM, which was comparable with that of the positive controls. Furthermore, compound 12 regulated the expression of cell cycle‐related proteins (Cyclin B1, Cdc25c, and Cdc2) and apoptosis‐related proteins (Bcl‐2, Bcl‐x, and Mcl‐1). Mechanistically, compound 12 could arrest cell cycle at the G2/M phase, thus induce an increase of apoptotic cell death. In addition, molecular docking hinted the possible interaction mode of compound 12 into the colchicine binding site of tubulin heterodimers. According to the applications of microtubule‐targeting agents in both direct and synergistic cancer therapies, we hope this work might be of significance for future researches. [ABSTRACT FROM AUTHOR]