A new series of 4-(4-(substituted)-1H-1,2,3 triazol-1-yl)-N-phenethylbenzenesulfonamide derivatives 5 were synthesized through the Click approach and evaluated for their cytotoxic activity against four cancer cell lines (HuCCA-1, HepG2, A549, and MOLT-3). Most of the synthesized triazoles 5 displayed cytotoxicity against MOLT-3 cell line, except for analogs 5a–c and 5e. Significantly, 4-phenyltriazoles (5a and 5n), 4-(naphthalen-2-yloxy) methyltriazole 5d, as well as 4-((2-oxo-2H-chromen-7 yl)oxy)methyltriazole 5l showed higher cytotoxic activity against HepG2 cells than the reference drug, etoposide. Interestingly, the 4-phenyltriazole 5a was the most potent and promising compound with IC50 value of 9.07 lM against HepG2 cell line. The analog 5a also exerted the highest cytotoxic activity against HuCCA-1 cells. This finding provides the novel lead molecules for further development.