A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c &8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, <sup>1</sup>H NMR, <sup>13</sup>C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC<sub>50</sub> 7.41 + 0.8 μM), SKNSH (IC<sub>50</sub> 8.68 + 1.1 μM), MCF-7 (IC<sub>50</sub> 9.76 + 1.3 μM) and MDA-MB-231, while compounds 7a and 7b showed promising anti-proliferation against above four human cancer cell lines with IC<sub>50</sub> 7.95-11.62 μM, respectively, compared with the standard drug Doxorubicin. We explored the probable key active site and binding mode interactions in HDAC8 (PDB ID:3SFH) and EHMT2 (PDB ID:3K5K) proteins. The docking results are complementary to the experimental observations.