Neoplastic growth of the breast is the most common malignancy in women worldwide and its incidence has increased in most countries. In this study, we have evaluated the efficacy of Pleurotus ostreatus (Jacq. Ex Fr.) P.kumm. (P. ostreatus) an edible mushroom on modulating levels of xenobiotic metabolizing en- zymes, hormonal status of estrogen and progesterone receptor (ER/PR), protein expressions and histo- pathological analysis in 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinogenesis using a rat model. DMBA was induced by single subcutaneous injection at a dosage of 25 mg in 1 mL vehicle. The ethanolic extract of P. ostreatus (POEet) was administered orally at a concentration of 600 mg/kg bwt as pre- and post-initiation stage of treatment throughout the experimental period which was also compared with standard tamoxifen (TAM) (10 mg/kg bwt). At the end of 16 weeks, our results showed the elevated phase I and depleted phase II metabolizing enzymes, over expression of (ER/PR) and the expression pattern of the proteins such as fas, fasL, caspase 3, caspase 8, caspase 9, Bax were found to be down regulated whereas p53, Bcl2, cox-2 and cyclin D1 were markedly upregulated in DMBA-induced Sprague-Dawley rats, which were significantly reversed on P. ostreatus administration. Moreover, pre- treatment with P. ostreatus showed improved response when compared to that of posttreatment. Based on scientific appraisal, we conclude that the dietary consumption of P. ostreatus might offer maximum protection against DMBA-induced mammary carcinogenesis and improving human health if used as a regular basis.