Twenty-three new coumarin-furoxan hybrids were synthesized, which exhibited nanomole antiproliferation activities in A2780, A2780/CDDP, MCF-7/ADR, and MDA-MB-231. Among them, compound <b>9</b> showed the strongest collateral sensitivity to MCF-7/ADR with 499-fold potency compared with MCF-7. Notably, the solubility of compound <b>9</b> increased 70-fold compared with the lead <b>2</b>. And preliminary pharmacological studies displayed that compound <b>9</b> obviously increased Rh123 accumulation in MCF-7/ADR and released NO to produce ROS in lysosomes, which were able to damage lysosomal membrane and induce apoptosis. These results reasonably explained that the collateral sensitivity of compound <b>9</b> to MCF-7/ADR was closely related to P-gp-mediated lysosome damage and apoptosis. Additionally, compound <b>9</b> showed a very weak cytotoxicity both in MCF-10A and hERG potassium channels and had a desirable safety in ion cyclotron resonance (ICR) mice. Hence, compound <b>9</b> was merited to further study for developing a desirable candidate against MDR MCF-7/ADR via a potential mechanism of collateral sensitivity in MDR cancer cell lines.