Aim: Breast cancer is the most common malignancy in women worldwide. Therefore, there is a need to define new strategies that can overcome the deficiencies of existing treatments. In our study, we aimed to define new herbal combination therapies that can be used to target breast cancer cells. For this purpose, we investigated the cytotoxic, apoptotic, anti-proliferative and cell cycle regulatory effects of Centaurea calolepis (CCI), Origanum sipyleum (OSM) and Phlomis lycia (PLI) plant extracts in combination with ponatinib on MCF-7 cells. Materials and Methods: The cytotoxic effects of OSM, CCI, PLI and ponatinib on MCF-7 cells were measured in real time by xCELLigence. The median-effect equation was used for the analysis of combinations of ponatinib with CCI (p-CCI), OSM (p-OSM), PLI (p-PLI). Apoptosis, proliferation and cell cycle regulation were evaluated by flow cytometry. Results: The IC50 doses of CCI, OSM and PLI extracts in MCF-7 cells were calculated as 59.5, 57, 44.2 μg/ml at 48 hours and 51.6, 54.21, 42.52 μg/ml at 72 hours, respectively. Combination analyses revealed that p-CCI was additive, p-OSM and p-PLI showed a moderate synergistic effect at 48th hours. It was determined that apoptosis induced by ponatinib was significantly increased with the combinations of CCI and PLI. CCI and PLI treatments exhibited moderate anti-proliferative effects on MCF-7 cells, while OSM extract suppressed proliferation most significantly. Consistent with the proliferation results, the highest G0/G1 arrest was observed with OSM treatment. It was revealed that combined p-CCI and p-PLI treatments significantly increased the anti-proliferative effect of ponatinib and caused a higher level of G0/G1 accumulation. Conclusion: Combinations of ponatinib and CCI, OSM, PLI plant extracts exhibited anti-cancer activity in breast cancer with induction of apoptosis, suppression of proliferation and cell cycle arrest. In light of the high anti-cancer effects identified, extracts of these Turkish endemic plants may represent a potential strategy in the treatment of breast cancer patients.