ABSTRACT:Trastuzumab deruxtecan (T‐DXd) significantly improves outcomes in HER2‐positive or low metastatic breast cancer (MBC), but systematic documentation of its myotoxicity is lacking. A 45‐year‐old woman with HER2‐low MBC and normal body composition (BMI 22.9 kg/m2, visceral adipose area [VAT] 69.1 cm2) developed T‐DXd myopathy. She experienced dysphagia, Grade III myalgia, and creatine kinase (CK) peak of 1755 U/L, with MRI confirming lumbar subcutaneous edema and paraspinal muscle swelling. T‐DXd was discontinued. Supportive therapy included hydration, urine alkalization by sodium bicarbonate, glutathione, and magnesium isoglycyrrhizinate. By Day 8, CK decreased to 539 U/L with myalgia improvement. After 13 days off therapy, CK rebounded to 1735 U/L with Grade III myalgia, which resolved upon reinitiating support. This case report presents the first documented instance of severe T‐DXd‐related myopathy in a patient with normal body composition. The observed case outcomes suggest that the combination of glutathione and magnesium isoglycyrrhizinate could potentially reduce CK levels and alleviate T‐DXd‐associated muscle pain. However, the observed clinical efficacy is based on an individual case. Extrapolation of these clinical outcomes requires large‐scale randomized controlled trials with rigorous covariate adjustment.