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A series of novel 1,2,4-triazole-chalcone compounds 10a–10s were designed by molecular hybridization strategy and synthesized. The molecular structures of the novel chalcones were characterized by 1H-NMR, 13C-NMR, and HRMS. The anti-proliferative activities of the novel chalcones against four cancer cell lines in vitro were examined by MTT, four tumor cell lines including human colon cancer cell SW620, human non-small cell lung cancer cell A549, human cervical cancer cell HeLa, and human breast cancer cell MCF-7. Compound 10o showed certain selectivity to SW620 cell line, and its IC50 value was 21.55 μM. 10q had good anti-proliferative activity against A549 cells with an IC50 value of 25.58 μM.