Highly pathogenic avian influenza viruses (HPAIV), such as H5N1, H5N6, and H7N9, have been reported to frequently infect humans, but acute encephalitis caused by HPAIV in humans has been rarely reported. We report the first critical case of acute encephalitis with mild pneumonia caused by the H5N6 virus. On January 25 of 2022, a 6-year-old girl with severe neurological symptoms was admitted to our hospital and rapidly developed into 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 that belonged to clade 2.3.4.4b. This patient was diagnosed with acute encephalitis and discharged from the hospital accompanied by a language barrier. An epidemiological investigation confirmed that wild waterfowls were the direct source of infection in this case. Our study highlights the urgent need to pay attention to acute encephalitis caused by HPAIV.