Breast cancer is a global public health problem where it is the second most prevalent cancer. Historical cancer treatment with graviola has been reported. This study aimed to investigate the protective effects of graviola on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat breast cancer. Fifty female Wistar rats were allocated into four groups: control group (gastro-gavaged by sesame oil), DMBA-treated group (gastro-gavaged a single dose of DMBA [50 mg/kg body mass, diluted in 1 ml sesame oil]) at the age 57 days, DMBA+G37-treated group (gastro-gavaged a single dose of DMBA [50 mg/kg body mass, diluted in 1 ml sesame oil]) at the age of 57 days plus graviola (200 mg/kg body mass) two times weekly (p.o.) at the age of 37 days till the end of the experiment, and DMBA+G57-treated group (received a single dose of DMBA [50 mg/kg body mass, diluted in 1 ml sesame oil]) plus graviola (200 mg/kg body mass) two times weekly at the age of 57 days until the end of the experiment. After the 30-week experimental period, blood samples were collected. Then, animals were sacrificed to determine the apoptotic indices, antioxidant status, and mammary gland tumor marker (CA 15-3). The DMBA upregulated the expression of one of the main anti-apoptotic genes: B-cell lymphoma protein 2 (BCL2) and estrogen receptor alpha (ER-α) gene. Moreover, it significantly increased breast lipid peroxidation and serum CA 15-3 but decreased breast antioxidant enzymatic activities (glutathione peroxidase, glutathione S-transferase, catalase, and superoxide dismutase). Nevertheless, administration of DMBA and graviola especially DMBA+G37 induced apoptosis through at least 1.5-fold in gene expression levels of pro-apoptotic genes: BCL2-associated X protein (BAX), tumor suppressor gene (P53), and cysteinyl-aspartic acid-protease-3 (caspase-3). A critical role of P53 in the regulation of the BCL2 and BAX has been reported. These proteins can determine if the cell undergoes apoptosis or cancels the process. Once the BAX gene activates caspase-3, there is no irreversible way toward cell death. Also, graviola ameliorated the DMBA effects on antioxidant enzymatic activities and tumor marker CA 15-3. This study concludes that graviola ameliorated DMBA-induced breast cancer potentially through upregulating apoptotic genes, downregulating the ER-α gene, increasing antioxidants, and decreasing lipid peroxidation levels.