<p>Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Tamoxifen (TX) is widely used for the treatment of estrogen receptor–positive (ER⁺) breast cancer; however, the development of drug resistance limits its long-term therapeutic effectiveness. Fisetin (Fis) and chrysin (Chry) are naturally occurring flavonoids that have demonstrated anticancer properties, including inhibition of cell proliferation and migration and induction of apoptosis. In this study, we evaluated the anticancer effects of Fis and Chry, individually and in combination with TX, in ER⁺ MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines. Cells were treated with varying concentrations of Fis or Chry alone or in combination with TX. Cell viability was assessed using the MTT assay, while migratory and clonogenic capacities were evaluated by wound-healing and colony formation assays, respectively. Apoptosis was analyzed by flow cytometry, and the expression of invasion-related genes (MMP2 and MMP9) was quantified using real-time PCR. The results showed that Fis, Chry, and TX individually reduced cell viability, migration, and colony formation in both cell lines. Notably, combination treatments exerted significantly stronger cytotoxic and pro-apoptotic effects compared to single-agent treatments. Combination index (CI) analysis revealed CI values below 1, indicating a synergistic interaction between TX and the flavonoids. Furthermore, co-treatment markedly downregulated MMP2 and MMP9 expression. Collectively, these findings demonstrate that fisetin and chrysin enhance the anticancer efficacy of tamoxifen through synergistic mechanisms in breast cancer cells.</p>