Background: Pediatric coronavirus disease (COVID-19)-associated encephalopathy can lead to severe neurologic complications. However, data comparing it with other infectious encephalopathies are limited. This study aimed to compare the clinical characteristics of COVID-19-associated encephalopathy with those of influenza-associated encephalopathy, which serves as a representative model of severe infectious encephalopathy in Japan. Additionally, we assessed the factors associated with a poor prognosis. Methods: We conducted a retrospective cohort study of patients with COVID-19- and influenza-associated encephalopathy admitted to 7 children’s hospitals in Japan between January 2017 and December 2023. Clinical characteristics were compared using the Mann–Whitney U test and Fisher exact test. Additionally, logistic regression analysis was performed to identify factors associated with a pediatric cerebral performance category score ≥4 at discharge. Results: A total of 89 patients were included: 29 in the COVID-19 group and 60 in the influenza group. Demographics and initial clinical characteristics were similar between groups. However, a significantly higher proportion of patients in the COVID-19 group had a pediatric cerebral performance category score ≥4 at discharge (37.9% vs. 16.7%, P = 0.04). In each of the 3 separate multivariable models, COVID-19, the presence of underlying neurologic conditions and shorter time from onset to encephalopathy diagnosis were independently associated with poor prognosis. Conclusions: The clinical characteristics of the 2 groups were similar; however, patients with COVID-19-associated encephalopathy showed worse discharge neurologic outcomes, warranting cautious interpretation. Enhancing public awareness of the severe outcomes and conducting further research is essential for better understanding its pathogenesis and treatment.