Antibody–drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to poor macromolecule penetration across the blood–brain tumor barrier. Trastuzumab deruxtecan (T-DXd), a high-payload antibody–drug conjugate, was recently found to improve progression-free survival in HER2+ breast cancer patients versus prior-generation trastuzumab emtansine, prompting us to evaluate CNS activity in a woman with brain-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent, previously-irradiated lesions were biopsy-proven to represent treatment effect. Subsequent recurrence occurred upon treatment holiday; partial response was observed with rechallenge. This case suggests T-DXd is active in HER2+ breast cancer brain metastases and supports further prospective evaluation.