Natural bioactive compounds with apoptotic action might be a promising new anti-cancer drug source. The purpose of the present study was to assess the apoptotic, anti-proliferative, antioxidative activities of a therapeutic plant Datura metel in liver hepatocellular carcinoma, HepG2 cell lines, as well as in normal baby hamster kidney (BHK) cell lines as controls. Ethanol and n-hexane solvents were used to extract Datura metel leaves extract. Standard techniques for identifying components were used to conduct phytochemical analysis. Cell death and viability in all sets of the cells were assessed using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), trypan blue and crystal violet tests. For the estimate of apoptosis and cell death in all groups ELISA of Annexin-V was used. In addition, antioxidant enzyme activity assays were also conducted to estimate H2O2, nitric oxide, superoxide and DPPH radical scavenging activities. The outcomes revealed that when cancer cells from the HepG2 cell lines were treated with Datura metel extracts, they demonstrated decreased viability, proliferation, and enhanced apoptosis as compared to normal BHK cells and untreated control cells. Anti-oxidative scavenging activities were higher in cancer cells treated with Datura metel extract than in untreated ones. It was concluded that the Datura metel leaves extract induces apoptosis, enhance antioxidant status, decrease proliferation in HepG2 cells.