Memantine is used for neurocognitive protection in patients undergoing cranial radiotherapy for central nervous system tumors and is assumed to be well-tolerated. We present a case of memantine-induced altered mental status requiring intensive care unit admission. An adolescent male with relapsed, progressive medulloblastoma presented with severe altered mental status shortly after the first fraction of palliative whole brain radiotherapy. After extensive evaluation, his profound confusion was attributed to memantine, which had been initiated one week prior. Clinicians should be aware of the risk of altered mental status with memantine, given the increased utilization and upcoming clinical trials in pediatric patients.