Digestive system cancers represent a group of malignancies with high global incidence and a particularly heavy disease burden in China. Among these, gastric cancer, colorectal cancer, and biliary tract cancer represent critical human epidermal growth factor receptor 2 (HER2)-positive subtypes that require focused clinical attention. Antibody–drug conjugates (ADCs), which utilize HER2-targeted monoclonal antibodies to deliver cytotoxic agents directly to tumor cells, have revolutionized precision therapy in HER2-positive cancers, marking a significant milestone in oncologic treatment. Currently, trastuzumab deruxtecan and disitamab vedotin have been approved for the treatment of advanced gastric cancer. This expert consensus emphasizes the safety management of HER2 ADCs in digestive system cancers, considering the unique anatomical complexity and the vulnerability of the mucosal barrier in this system. It underscores the essential role of multidisciplinary team collaboration in standardizing the management of adverse events and offers evidence-based recommendations to guide clinical practice across primary and secondary care settings. Furthermore, it underscores the value of a “physician-led, patient-engaged” model in patient education. The safety management experience accumulated in this context also offers important insights for the clinical application of ADCs targeting other oncogenic pathways.