As <i>c-MYC</i> is one of the central players in triple-negative breast cancer (TNBC) oncogenesis, inhibiting <i>c-MYC</i> expression would be an effective anticancer strategy. Transcription-induced negative supercoiling is crucial in the regulation of <i>c-MYC</i> transcription, which facilitates the formation of a G4 structure in NHE III<sub>1</sub> that can silence the transcription. However, topoisomerase 1 (Topo1) can dissipate this negative supercoiling, leading to continuous activation of <i>c-MYC</i> transcription. Thus, dual ligands targeting both Topo1 and <i>c-MYC</i> G4 appear to be significant in cancer therapy. In this study, a series of new dibenzoquinoxaline derivatives were designed, synthesized, and evaluated for both Topo1 and <i>c-MYC</i> inhibition. Among them, <b>5</b> was identified as the most promising dual ligand, which could effectively inhibit Topo1 activity and strongly stabilize <i>c-MYC</i> G4, thereby inhibiting cancer cell growth. Accordingly, this work suggests that this dual-targeting strategy may be effective in cancer therapy.