Background and Clinical Significance: Acute necrotizing encephalopathy (ANE) represents a severe complication of influenza virus infection, mainly described in children. We report the cases of two young girls with ANE associated with influenza virus infection, diagnosed by MRI cerebral scan. Case Presentation: A 7-year-old girl with a history of a previous episode of ANE presented with a worsening soporous state and seizures. In the second case, an otherwise healthy 5-year-old girl presented with fever, seizures and marked neurological deterioration. In both cases, nasopharyngeal swab testing was positive for influenza virus A, while cerebral MRI indicated ANE. Despite aggressive treatment with high-dose corticosteroids and a five-day course of immunoglobulins, the ultimate prognosis was poor in both patients. ANE is a serious complication of viral infections in children, with a high mortality rate and a broad spectrum of neurological sequelae. To date, the pathophysiology and management of influenza virus-induced ANE remain uncertain. Although ANE is usually sporadic, familial and recurrent cases have been reported, and a RANBP2 mutation has occasionally been associated. Conclusions: Rapid recognition of neurological symptoms and suspicion of a viral trigger, especially in influenza-like illnesses, are both essential for the timely administration of effective therapy. Further research is needed to clarify the pathophysiology of ANE and establish the best therapeutic strategies to fight such a deadly disease.