A series of 1,2,3-triazole-chalcone hybrids were designed, synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (SK-N-SH, HepG-2 and MGC-803). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Particularly, compound 12k showed the most excellent antiproliferative activity with an IC50 value of 1.53 µM against SK-N-SH cancer cells. The mechanism studies revealed that compound 12k inhibited the proliferation of SK-N-SH cancer cells by inducing apoptosis and arresting the cell cycle at G1 phase.