Current clinical ways include the usage of medicinal plants as therapeutic agents in a large scale of applications. The present study is focused on the anticancer activity of the methanolic extract of Atriplex halimus and the likely underlying mechanisms were also investigated. Results exhibited that the extract had an antiproliferative effect and highly cytotoxicity in cancer cells, Human hepatocellular carcinoma (HepG2) (IC50 = 54.86 μg/ml), against the human breast adenocarcinoma cell line (MCF-7) with IC50 value of 153.6 μg/ml and lung cancer cell line (A549) (IC50 = 101.9 μg/ml). In contrast, this extract exhibited no induces growth inhibition (did not cytotoxic activity) on normal cell lines. Flow cytometric analysis of propidium iodide staining detected that the treatment of HepG2 cells with A. halimus led to increase G2/M phase cell cycle arrest. The data obtained from acridine orange/ethidium bromide(AO/EtBr) protocol showed the morphological characters of apoptosis such as apoptotic bodies, nuclear fragmentation and chromatin condensation; in addition, necrotic cells were observed. The real time-PCR and western blotting techniques were used to measure the mRNA levels of p53, Bax, and Bcl-2 genes and proteins expression. The apoptotic process triggered by A. halimus involved the upregulation of p53 and Bax and the downregulation of Bcl-2 in both techniques. These data indicated that A. halimus exhibited antiproliferative effect by a cell cycle blocking at the G2/M phase and apoptosis mediated cytotoxicity in carcinoma cells. In conclusion, these results suggest that A. halimus could be a good candidate species as a natural source of anticancer agents.