Ticagrelor synergistically enhanced the cytotoxicity of Adriamycin (Adr) and Paclitaxel (PTX) in MCF-7/Adr and MCF-7/PTX cells, respectively. In conclusion, Ticagrelor reverses breast cancer MDR by concurrently inhibiting PI3K/AKT/mTOR signaling, downregulating ABCB1 expression and function. Our findings highlight the potential of Ticagrelor as a dual-acting agent that not only targets tumor metastasis but also overcomes chemoresistance, providing a new strategic direction for combination therapy in refractory breast cancer.