This study presents novel findings on the potential of phloretin, an apple polyphenol, to enhance the effectiveness of anti-human epidermal growth factor receptor-2 (HER2) antibody therapy in HER2-positive breast cancer patients. Our research reveals that phloretin inhibits type II glucose transporter (GLUT2) activity, significantly reducing cancer cell glucose uptake. We confirmed the overexpression of GLUT1 and GLUT2 mRNA in paired human breast tumor tissues, with GLUT2 overexpression associated explicitly with poorer survival rates in breast cancer patients. Treatment with phloretin was observed to increase the interaction between GLUT2 and HER2 proteins, attenuate glycolysis, and enhance the binding affinity of anti-HER2 antibody drugs to target human breast cancer cells. Furthermore, the efficacy of the combination therapy involving phloretin and antibody drugs was reaffirmed in a cell-derived xenograft tumor animal model, particularly in suppressing the growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. These significant findings suggest that targeting GLUT2 activity with phloretin in combination with anti-HER2 antibody drugs may help mitigate the development of drug-resistant breast cancer, offering valuable insights for enhancing tumor treatment strategies and contributing to developing more effective therapies.