Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased apoptosis, which was confirmed by using an Annexin-V/PI assay. Interestingly, NSC260594 treatment reduced the cancer stem cell (CSC) population in TNBCs. To make NSC260594 more clinically relevant, we treated NSC260594 with TNBC cell derived xenograft (CDX) mouse model, and with patient-derived xenograft (PDX) organoids. NSC260594 significantly suppressed MDA-MB-231 tumor growth in vivo, and furthermore, the combination treatment of NSC260594 and everolimus acted synergistically to decrease growth of TNBC PDX organoids. Together, we found that NSC260594 might serve as a lead compound for triple-negative breast cancer therapy through targeting Mcl-1.