Digestive system cancers are very prevalent globally. Among these, human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, colorectal cancer, and cholangiocarcinoma are tumors that require particular attention. HER2-targeted antibody-drug conjugates (ADC) deliver cytotoxic drugs specifically to tumor cells via HER2 monoclonal antibodies, representing a breakthrough in the precision treatment of HER2-positive tumors and a milestone in oncology therapeutics. Currently, trastuzumab deruxtecan and disitamab vedotin have been approved by the National Medical Products Administration for the treatment of advanced gastric cancer. However, with the expanding clinical use of ADC, drug-related adverse reactions have been increasingly observed, impacting patient prognosis and quality of life. Based on clinical trial evidence from China and abroad, and integrating multidisciplinary expertise, this consensus emphasizes a “physician-led and patient-engaged” education model, defines key aspects of clinical management and patient education for HER2-targeted ADC-related adverse reactions, and provides evidence-based support for standardized management in primary healthcare settings.