Background & Objective: Canonical WNT/Wingless pathway regulates expression of target genes by modulating intracellular β-catenin leading to cancer growth and survival. Here, we studied inhibition of β-catenin using zerumbone (ZER) or β-catenin-siRNA in Sprague-Dawley rat cancer model. Methodology: Rat mammary gland tumor model was induced with the wild-type LA7 breast cancer cell line or β-catenin-knockdown-LA7 cells. LA7-rats were treated with ZER or β-catenin-siRNA as a positive control and the levels of β-catenin expression and its target gene were assessed using real-time PCR, immunohistochemistry and TUNEL assay. Results: We found good correlation between β-catenin inhibition and induction of apoptosis when using ZER or β-catenin-siRNA. In this aspect, ZER and β-catenin-siRNA inhibited cellular proliferation as reflected by reduced growth of breast cancer and apoptosis induction in rat mammary gland tumor. Further, our studies demonstrate that treatment with ZER and β-catenin-siRNA affected β-catenin-dependent gene expression. β-catenin downregulation by ZER or knockdown by β-catenin-siRNA improves the morphological and histological feature of the breast tissues as confirmed by subtle changes of the genes involved in cell-apoptotic pathways. Conclusion: This indicates that ZER targets similarly to β-catenin-siRNA and possibly be a useful anti-breast cancer by affecting expression of down-stream targets that are key components in cancer development. ZER can be a promising anticancer candidate for treatment of breast.