A series of unreported dual-receptor inhibitors targeting both the tubulin colchicine site and AhR were designed and synthesized, and their anti-breast-cancer activities were evaluated. Compound <b>12</b> showed the strongest activity with an IC<sub>50</sub> of 0.9 nM in MCF-7 cell lines. Besides, <b>12</b> could significantly inhibit cancer growth in MCF-7 xenograft tumor models with no obvious toxic effects and was more effective than the positive control (combretastatin A-4). With the in-depth study, it was found that <b>12</b> could induce apoptosis in breast cancer cells by making arrest in G2/M phase, depolarizing mitochondria and inducing intracellular reactive oxygen generation. This evident anticancer effect and the ability to inhibit cell migration were attributed to the synergistic antagonism of 12 on tubulin and AhR. In general, <b>12</b> was worthy of further research as an effective and safe anti-breast-cancer drug.