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In patients with triple‐negative breast cancer (TNBC), evidence suggests that tumor‐initiating cells (TIC) have stem cell‐like properties, leading to invasion and metastasis. HSP90 plays a critical role in the conformational maintenance of many client proteins in TIC development. Therefore, we hypothesize that the novel C‐terminal HSP90 inhibitors KU711 and KU758 can target TIC and represent a promising strategy for overcoming metastasis. Human breast cancer cells (MDA‐MB‐468LN, MDA‐MB‐231) treated with the HSP90 inhibitors KU711, KU758, and 17‐AAG showed a 50–80% decrease in TIC markers CD44 and aldehyde dehydrogenase (P < 0.01) as assessed by flow cytometry. A decrease in sphere formation, which was used to assess self‐renewal, was observed after the treatment of TNBC cells starting at 2.5 µm KU711 and 0.31 µm KU758. KU compounds also blocked the invasion and migration of TNBC cells in a dose‐dependent manner. The knockdown of HSP90 clients was observed without any change in prosurvival HSP70 levels. In vivo, in a murine orthotopic breast cancer model, treatment with KU758 and KU711 yielded an approximately twofold and a fourfold reduction in tumor volumes versus control, respectively, without demonstrated toxicity. In conclusion, C‐terminal HSP90 inhibitors are potent novel therapeutics against TNBC in vitro and in vivo as they target TICs and block invasion, EMT transition, and self‐renewal. C‐terminal HSP90 inhibitors KU711 and KU758 reduce tumor growth of triple‐negative breast cancer xenografts by targeting Akt/mTOR and MAPK/ERK pathways, cancer stem cells, migration, and EMT transition.