Doxorubicin is widely used for treating patients with leukemia. However, chemotherapy efficacy is frequently undermined by multidrug resistance (MDR), driven by overexpression of drug efflux pumps. Therefore, combination therapies are actively investigated to overcome resistance and expand treatment options. In this study, 3,200 compounds were screened, and finally the orally bioavailable multikinase inhibitor sitravatinib was identified to resensitize doxorubicin-resistant K562 chronic myelogenous leukemia cells to doxorubicin. Synergistic activity of the sitravatinib-doxorubicin combination was confirmed using Compusyn (CI<1) and SynergyFinder (Bliss, score>10) analysis. Additionally, this combination enhanced caspase-3/7-dependent apoptosis. Considering that sitravatinib inhibited ABCB1 ATPase activity in human carcinoma and colon cancer cells. Its synergistic anticancer activity could result from its potential to inhibit ABCB1 ATPase activity in doxorubicin-resistant K562 cells. In conclusion, the sitravatinib-doxorubicin combination, overcoming multidrug resistance and enhancing apoptosis, could be a promising therapeutic strategy for treating patients with chemo-resistant leukemia.​