The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (<b>1</b>). Among the new compounds, <b>a6</b> with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and <b>1</b> in TNBC cells. Remarkably, <b>a6</b> caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, <b>a6</b> significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.