Objective To summarize the clinical characteristics, diagnosis and treatment and prognosis of acute necrotizing encephalopathy of childhood (ANEC). Methods The clinical data of ANEC patients from June 2016 to December 2022 were retrospectively analyzed. Survivors were followed up through telephone. Survivors' life quality was measured using the pediatric overall performance category scale (POPC). Results A total of 26 children with ANEC were included, with a male to female ratio of 1.6:1 and a median age of 36.0 (23.0-69.0) months. The most common season was summer (42.3%), followed by winter (34.6%). Influenza virus was the most common preceding infection (34.6%), followed by human herpesvirus 6B and SARS-CoV-2. All patients had fever and different degrees of consciousness disorder, and 24 had convulsions. Symmetrical thalamic involvement (100%) was the typical change in imaging, with basal ganglia (50.0%), brainstem (61.5%), cerebellum (26.9%) and other sites involved. Twenty-three patients received methylprednisolone shock therapy, and the in-hospital fatality rate was 23.1% (6/26). The cumulative case fatality rate 6 months after discharge was 30.7% (8/26). The 14 surviving children were followed up regularly for 6 months, and 11 received rehabilitation treatment. One child received two points for the POPC, four received three, six received four, one received five, and two received six. The POPC results of 3 patients with ANEC after SARS-CoV-2 infection at 3 months follow-up were 2 in 2 children and 6 in one child. Conclusions ANEC occurs frequently in summer and winter in South China, and can be induced by SARS-CoV-2 infection. The typical signs of ANEC are fever, convulsion, and disturbance of consciousness, and the typical imaging changes were bilateral thalamic involvement. Early immunotherapy and comprehensive rehabilitation training can reduce the severity of neurological sequelae.