Tumor initiating cells (TIC) have been suggested as a mechanism for driving chemoresistance and tumor recurrence in human cancers including triple negative breast cancer (TNBC). Significant progress has been made in targeting TICs. However, methods for simultaneously targeting heterogeneous TIC populations are lacking. In this study, we found that treating TNBC cells with chemotherapeutic agents led to a significant accumulation of the ALDH+ TIC population. Treating TNBC cells with a disulfiram and copper mixture (DSF/Cu) specifically decreased the ALDH+ TIC population and treatment with BKM120, a pan-PI3K inhibitor, significantly decreased the CD44+/CD24- TIC population. Furthermore, treatment with DSF/Cu or BKM120 induced higher levels of apoptosis in ALDH+ or CD44+/CD24- populations, respectively, than in bulk tumor cells. Combining DSF/Cu and BKM120 treatment simultaneously decreased the ALDH+ and CD44+/CD24- TICs. Using a TNBC tumor xenograft mouse model, we found that DSF/BKM in combination with Taxol significantly reduced the tumor burden and delayed tumor recurrence compared to Taxol treatment alone. Our study is the first of its kind to use two different drugs to abolish two major TIC subtypes simultaneously and inhibit tumor recurrence. These results lay a foundation for developing a novel therapy that can improve chemotherapeutic efficacy.