Resistance to single or multiple chemotherapeutic drugs is a major obstacle in breast cancer therapy. Recent studies have suggested that GPR30 is implicated in mediating cancer cell proliferation. The aim of this study was to examine the anti-tumor effects of the GPR30 antagonist G15 in breast cancer. We found that low concentrations of G15 had little effect on breast cancer cell viability, but could enhance doxorubicin sensitivity in MDA-MB-231 and MCF-7 cells with epithelial phenotypes. In addition, G15 prevented epithelial breast cancer cells undergoing epithelial-mesenchymal transition (EMT) after doxorubicin induction. Moreover, downregulation of GPR30 suppressed the EMT in breast cancer cells. These results support that G15 enhanced doxorubicin sensitivity and prevented the EMT in epithelial breast cancer cells by inhibiting GPR30 expression.