Most of cancer chemotherapeutics and chemopreventives exert their effects by triggering apoptotic cell death. In this study, novel benzimidazole and benzothiazole derivatives have been synthesized to investigate their effects on HepG2 liver cancer cell lines after initial screening study. A dose response curve was constructed and the most active derivatives were further studied for apoptotic analysis. Six active benzimidazole derivatives (8, 9, 10, 12, 13 and 14) significantly induced apoptosis compared to control group. Two compounds 10 and 12 induced apoptosis by arresting cells in G1 phase of cell cycle which is confirmed by increased expression level of p21. The activity of caspase-3 which is well known as one of the key executioners of apoptosis was determined in the presence and absence of the tested derivatives. Our results indicated that compounds 10 and 12 significantly increased caspase-3 activity compared to control group. Moreover, a docked pose of compounds 10 and 12 was obtained bound to caspase-3 active site using Molecular Operating Environment module. This study demonstrated that benzimidazole derivatives 10 and 12 provoke cytotoxicity and induced apoptosis in liver cancer cells HepG2.