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[1,2,4]Triazolo[1,5-<i>a</i>]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-<i>a</i>]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds <b>H1</b>–<b>H18</b> against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound <b>H12</b> exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC₅₀ values of 9.47, 9.58 and 13.1 μM, respectively, which were more potent than that of the positive drug <b>5-Fu</b>. In addition, compound <b>H12</b> could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound <b>H12</b> exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound <b>12</b> induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-<i>a</i>]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, <b>H12</b>, might be a valuable hit compound for the development of anticancer agents.