There is a growing interest in using naturally-occurring compounds as cancer chemopreventive or chemotherapeutic agents. This study investigated the anticancer potential of the graviola fruit extract (GFE) on specific human breast cancer (BC) cells. GFE was found in our preliminary screening to selectively inhibit the growth of certain human BC cells (MDA-MB-468) but did not affect non-transformed breast epithelial MCF-10A cells. GFE treatment was very effective against the growth of MDA-MB-468 BC cells with an IC50 of 4.8 µg/ml. In vitro, effects of GFE treatment on MDA-MB-468 BC cells were further examined for apoptosis and cell proliferation. Apoptosis, determined qualitatively and quantitatively, was enhanced and accompanied by caspase-3 activation. GFE treatment also induced cell cycle arrest at the G1 cell cycle phase and significantly reduced the percentage of MDA-MB-468 cells in S-phase following 24h of exposure. Moreover, the results from analysis of the mRNA expression of epidermal growth factor receptor (EGFR), which plays an important role in regulating cell development and death, by qRT-PCR, suggested that GFE-induced selective growth inhibition of MDA-MB-468 BC cells is associated with a significant inhibition of EGFR gene expression in the cells. In vivo, dietary treatment with GFE significantly inhibited MDA-MB-468 tumor growth implanted in mice by reducing tumor wet weight and significantly reduced EGFR and p-ERK protein expression in tumors. Overall, GFE attenuated cell proliferation, induced apoptosis, modulated cell cycle regulation and downregulated EGFR gene expression both in vitro and in vivo. These discoveries support the further studies to fully elucidate the antitumor potential of GFE and its components as a dietary agent for BC.