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A series of novel indole hydrazide derivatives was synthesized and evaluated for their anticancer activities. Compound 12 exhibited the highest antiproliferative activity against the MCF‐7 cell line, with an IC50 value of 3.01 µM. Treatment of MCF‐7 cells with compound 12 led to cell cycle arrest at the G0/G1 phase and also displayed a significant annexin V binding pattern, indicating that compound 12 is effective in apoptotic cell death. The Western blot analysis showed that compound 12 increased the expression of proapoptotic Bax and decreased the levels of the antiapoptotic Bcl‐2 protein. It was also observed that MCF‐7 cells treated with compound 12 showed reduced levels of procaspase‐3 and ‐9 proteins. Moreover, compound 12 treatment induced a significant DNA damage in MCF‐7 cells by increasing H2AX and ATM phosphorylation.