Abstract: Antibody-drug conjugates (ADCs) represent a major breakthrough in the treatment of human epidermal growth factor receptor-2 (HER-2)-positive breast cancer as they are responsible for significantly improving clinical outcomes. However, their widespread use is accompanied by severe adverse effects that not only impact the quality of life of patients and treatment adherence but also life-threatening, ultimately leading to treatment discontinuation. This article systematically reviews the underlying mechanisms and management strategies for ADC-related toxicities in HER-2-positive breast cancer. Additionally, it focuses on key adverse events, including thrombocytopenia, interstitial lung disease, and cardiotoxicity, that are induced by ADCs such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Based on the clinical evidence, we proposed early monitoring and standardized intervention measures, emphasizing the importance of timely recognition and systematic management to mitigate risks. Furthermore, we explored future directions for optimizing ADC design to reduce their toxicity and provide valuable insights into their safe clinical application.