Objective To describe a novel case of COVID-19 associated acute necrotizing encephalopathy in a patient with aplastic anemia where there was early brainstem predominant involvement. Methods Evaluation of cause, clinical symptoms, and treatment response. Results A 59-year-old woman with a background of transfusion-dependent aplastic anemia, presented with seizures and reduced level of consciousness, 10 days following the onset of subjective fevers, cough, and headache. Nasopharyngeal swab testing for SARS-CoV-2 was positive and admission CT demonstrated diffuse swelling of the brainstem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient’s condition deteriorated and MRI on day 6 demonstrated worsening brainstem swelling with symmetrical hemorrhagic lesions in the brainstem, amygdalae, putamina and thalamic nuclei. Appearances were consistent with hemorrhagic acute necrotizing encephalopathy with early brainstem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission. Conclusions COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurological presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19 related neurological disease.