In January 2025, CDC received several reports of deaths among children aged <18 years with a severe form of influenza-associated encephalopathy (IAE) termed acute necrotizing encephalopathy (ANE). Because no national surveillance for IAE currently exists, CDC requested notification of U.S. pediatric IAE cases from clinicians and health departments during the 2024-25 influenza season, a high-severity season with a record number of pediatric influenza-associated deaths. Among 192 reports of suspected IAE submitted to CDC, 109 (57%) were categorized as IAE, 37 (34%) of which were subcategorized as ANE, and 72 (66%) as other IAE; 82 reports did not meet IAE criteria and were categorized as other influenza-associated neurologic disease. The median age of children with IAE was 5 years and 55% were previously healthy, 74% were admitted to an intensive care unit, and 19% died; 41% of children with ANE died. Only 16% of children with IAE who were vaccination-eligible had received the 2024-25 influenza vaccine. Health care providers should consider IAE in children with encephalopathy or altered level of consciousness and a recent or current febrile illness when influenza viruses are circulating. Annual influenza vaccination is recommended for all children aged ≥6 months to prevent influenza and associated complications, potentially including severe neurologic disease such as IAE and ANE.