The human epidermal growth factor receptor 2 (HER2)/erythroblastic oncogene B2 (ERBB2) is a tyrosine kinase receptor protein that plays an important role in the pathogenesis and aggressive nature of the tumors. It is well studied in various cancers, including breast, gastric, esophageal, ovarian, lung, and endometrial cancers. It is a well-known negative prognostic indicator in breast cancer associated with decreased disease-free survival and overall survival. Breast cancer treatment has been revolutionized with the invention of targeted monoclonal antibody therapies against the HER2 receptor, particularly trastuzumab and its antibody-drug conjugates (ADCs). HER2-targeted therapies have proven to improve progression-free survival and overall survival when added to chemotherapy in adjuvant, neoadjuvant, and metastatic settings in patients who are HER2-positive. ADCs approved for breast cancer include trastuzumab emtansine (Kadcyla, T-DM1) and trastuzumab deruxtecan (Enhertu, T-DXd). With enthusiasm and reported benefit, particularly in metastatic disease, HER2-targeted therapies are now widely used in breast cancer patients classified as HER2-negative based on binary classification but categorized as "HER2-low" with some degree of HER2 expression. HER2-targeted therapies are not approved for patients who have HER2 (ERBB2) mutation and have no HER2 expression of any degree (immunohistochemistry (IHC) 0+). We could not find any such reported cases, research studies, or clinical trials of HER2-targeted therapies being used in patients with HER2 mutation in our extensive search of the literature. We present a rare practice-changing case of a patient with triple negative metastatic breast cancer (estrogen receptor (ER), progesterone receptor (PR), and HER2 negative, HER2 0+ on IHC) and positive HER2 mutation, who achieved a disease-free survival of more than 2.5 years with trastuzumab deruxtecan monotherapy. This case makes a compelling argument for considering HER2-targeted therapies, mainly ADCs, in HER2-mutant breast cancer patients either as a monotherapy or in combination with other therapies, particularly in metastatic disease. This case report also indicates that further research and clinical trials looking into the efficacy and safety profile of anti-HER2 treatments in HER2-mutant breast cancers are warranted.