This study was designed to identify conditions that induce an increase in the sensitivity of drug-resistant cancer cells compared to sensitive cells. Using cell proliferation assays and microscopic observation, thioridazine (THIO) was found to induce higher sensitization in drug-resistant KBV20C cancer cells compared to sensitive KB parent cells. By studying cleaved PARP, annexin V staining, and Hoechst staining, we found that THIO largely increased apoptosis specifically in KBV20C cells, suggesting that the difference in sensitization between the resistant and sensitive cells can be attributed to the ability of THIO to induce apoptosis. THIO could also inhibit p-glycoprotein (P-gp) activity in the resistant KBV20C cells. These observations suggest that the mechanisms underlying THIO sensitization in resistant KBV20C cells involve both apoptosis and P-gp inhibition. Furthermore, co-treatment with THIO and vinblastine (VIB) induces higher sensitization in KBV20C cells than KB cells. As observed in a single treatment with THIO, the sensitization mechanism induced by the co-treatment also involves both apoptosis and P-gp inhibition. These results suggest that the THIO sensitization mechanism is generally conserved. Our findings may contribute to the development of THIO-based therapies for patients presenting resistance to antimitotic drugs.