Despite advances in cancer treatment, breast cancer remains one of the main life threatening diseases in women. Most anti-breast cancer drugs cause severe health complications and multidrug resistance. Although, some natural products, such as hesperidin (Hes), piperine (Pip) and bee venom (BV), showed anti-breast cancer effect when used separately, their combined effect together or with the anti-cancer drug tamoxifen (Tam) has not yet been studied. Herein, we hypothesized that these three natural products could potentiate the therapeutic effect of Tam when used together. First, we studied the cytotoxic effect of Hes, Pip, and BV on MCF7 and T47D cells using MTT assay and found reasonable IC₅₀ comparable to that of Tam. Second, we checked the effect of all combinations (n = 67 for each cell line, prepared as non-constant ratio from fractions of IC₅₀ of the four compounds) and found enhanced anti-proliferative effects on MCF7 and T47D and synergistic effect, revealed by combination index (CI) values below one. Next, the best 5 combinations with lowest Tam doses and CI but with highest cell death were selected for further molecular analysis in comparison to single-drug treatment. All single- and combined-treated groups showed a significant increase in apoptosis (indicated by upregulated mRNA level of the pro-apoptotic marker Bax and downregulated mRNA level of the anti-apoptotic marker Bcl2) and a significant decrease in mRNA level of the two breast cancer related receptors EGFR and ERα, with the best effect in combined groups especially that contained the 4 compounds, as compared to vehicle-treated group. Moreover, Pip, BV and all combinations, except Tam + Hes group, arrested MCF7 and T47D in G2/M phase of cell cycle, while Tam and/or Hes caused G0/G1 phase arrest. These results indicate that Hes, Pip and BV synergistically enhance the anti-cancer effect of Tam and could be used as safe adjuvant/vehicle to Tam in treatment of breast cancer after further confirmatory in vivo investigations.