Novel human astrovirus (HAstV) strains have been recently shown to cause fatal encephalitis in immunocompromised patients. We report two cases from our institution. A 2-year old female undergoing treatment for acute lymphoblastic leukemia and a 9-year old male with refractory acute myeloid leukemia. Both were found to have HAstV-VA1 in the cerebrospinal fluid (CSF) by metagenomics next generation sequencing (m-NGS) after the initial evaluation did not reveal any etiology. Patient 1 remains alive, in remission, showing gradual neurological improvement after treatment with steroids, intravenous immunoglobulin, ribavirin, nitazoxanide and Peg-INF-alpha 2b. Patient 2 died 7 weeks later while receiving palliative care.