<p>Breast cancer is a leading cause of cancer and death in women. There is an urgent need to explore medicinal compounds that can enhance therapeutic effectiveness while minimizing toxicity. The present study utilized lupeol and enzalutamide combinations in luminal and triple-negative breast cancer cells to assess their efficacy on cell proliferation, apoptosis, and cell cycle progression. We performed a cell viability assay to investigate cytotoxicity using the spectrophotometric method. A combination index analysis was performed to determine synergistic dose drug combinations. Apoptosis and cell cycle analysis were performed using flow cytometry. The mRNA expression was analyzed by RT-PCR. Results indicate that lupeol + enzalutamide (Lup + Enz) significantly reduces cell viability in cancer cells compared to the treatment alone. The Caspase Glo assay revealed that Lup + Enz increased the activities of caspase 3/7 and 9 in the breast cancer cell line. Furthermore, Lup + Enz induces G1 phase arrest (≈75%) and promotes apoptosis (20%) in MCF-7 cells. mRNA expression suggests that Lup + Enz activates apoptotic mRNA expression (≈ 0.25 to threefold) in cancer cells. In conclusion, lupeol, in combination with enzalutamide, alters various hallmarks of breast cancer, like proliferation, apoptosis, and cell cycle arrest. Thus, lupeol may be a promising agent that enhances the outcomes of enzalutamide-based therapy. Further preclinical and clinical research is needed to validate the findings of this study.</p>