HER2 mutations have been shown to be targetable in select cases of salivary gland cancers with overexpression or amplification of the HER2 oncogene. Fam-trastuzumab deruxtecan, a novel antibody-drug conjugate that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated efficacy as a third-line agent in HER2-overexpressing breast cancer after trastuzumab failure. These promising results in breast cancer suggest a potential paradigm for use in other tumors with known HER2 alterations, including salivary gland cancer. This report describes a 67-year-old man with HER2-positive metastatic parotid gland carcinoma who experienced disease progression after parotidectomy with adjuvant cisplatin-based chemoradiation, neratinib, and ado-trastuzumab emtansine. After disease progression on the latter HER2-directed therapy, his malignancy demonstrated complete response to fam-trastuzumab deruxtecan, which has been sustained for the past 7 months. Fam-trastuzumab deruxtecan appears to be a well-tolerated therapeutic option in patients with HER2-positive salivary gland carcinoma, with activity demonstrated after progression on ado-trastuzumab emtansine and HER2-directed kinase inhibition. Further studies should be conducted to explore the use of this agent in HER2-positive salivary gland cancers.