The study investigated the cytotoxic effect of a natural polyphenolic compound Tannic acid (TA) on human liver hepatocellular carcinoma (HepG2) cells and elucidated the possible mechanisms that lead to apoptosis and oxidative stress HepG2 cell. The HepG2 cells were treated with TA for 24 h and various assays were conducted to determine whether TA could induce cell death and oxidative stress. The cell viability assay was used to determine the half maximal inhibitory concentration (IC50), caspase activity and cellular ATP were determined by luminometry. Microscopy was employed to determine deoxyribonucleic acid (DNA) integrity, while thiobarbituric acid (TBARS) and nitric oxide synthase (NOS) assays were used to elucidate cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively. Western blotting was used to confirm protein expression. The results revealed that tannic acid induced caspase activation and increased the presence of cellular ROS and RNS, while downregulating antioxidant expression. Tannic acid also showed increased cell death and increased DNA fragmentation. In conclusion, TA was able to induce apoptosis by DNA fragmentation via caspase-dependent and caspase-independent mechanism. It was also able to induce oxidative stress, consequently contributing to cell death.