Acute necrotizing encephalopathy (ANE) is influenza-associated encephalopathy (IAE) that mostly occurs in younger age groups following an acute viral illness with a very low recovery rate. It is a rare but rapidly progressive neurodegenerative disorder which pathogenesis is still not clear. There are some cases reported where the virus can directly invade the central nervous system (CNS) through the peripheral nervous system. Several pathogenic conditions like rising levels of proinflammatory cytokines, dissolving the blood-brain barrier (BBB), etc can trigger the viral infection. There are no specific treatments available but initial steroid therapy in combination with antivirals and hypothermia therapy were found efficacious in some cases. Similarly, coronavirus disease 2019 (COVID-19) encephalopathy is caused by a novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2). Having a very low recovery rate, and still unknown pathophysiology, this condition is proved to be fatal for immunocompetent adults. Treatments are not available but drugs like remdesivir, hydroxychloroquine, tocilizumab, and losartan were used to reduce the viral infection. No recurrent cases have been reported so far, but reinfection of the virus can trigger hypoxic encephalopathy. This review mainly focuses on a comparative study to understand the pathophysiology to help for discovering a new area of drug development.