Highly pathogenic avian influenza virus (HPAIV) such as H5N1, H5N6, and H7N9 have been reported to frequently infect human, but acute encephalitis caused by HPAIV in human have been rarely reported. We report the first critical case of acute encephalitis with mild pneumonia caused by H5N6 virus. On January 25 of 2022, a 6-year-old girl with severe neurological symptoms was admitted to our hospital and rapidly developed to seizures and coma. Brain imaging showed abnormalities. Electroencephalogram (EEG) presented abnormal slow waves. Cerebrospinal fluid (CSF) contained elevated protein (1.64 g/L) and white cells (546×106/L). Laboratory investigations revealed abnormally elevated transaminases, lactate dehydrogenase and cytokines in serum. A novel reassortant H5N6 virus was identified from the patient´s serum, CSF and tracheal aspirate specimens. Phylogenic analysis indicated that this virus was a novel reassortant avian-origin influenza A (H5N6) virus belonged into clade 2.3.4.4b. This patient was diagnosed with acute encephalitis and discharged from the hospital accompanied with language barrier. Epidemiological investigation confirmed that wild waterfowls were the direct source of infection of this case. Our study highlights the urgent need to pay attenuation to acute encephalitis caused by HPAIV.