Encephalitis is an inflammatory disease of the brain that can lead to significant disruptions in brain function. It can be classified into infectious and non-infectious, with viruses being the most common pathogen in children. This study aims to provide a descriptive epidemiological analysis of encephalitis cases in children and adolescents treated at the University Hospital for Infectious Diseases "Dr. Fran Mihaljević" between 2006 and 2023. Additionally, it compares the probability of determining the etiology across three different periods, considering the implementation of panels for autoimmune encephalitis diagnostics and multiplex PCR panels for meningitis/encephalitis. The study included data from 243 children and adolescents hospitalized at the Department of Pediatric Infectious Diseases, with an average age of 8 years old. The findings revealed that the etiology was successfully identified in 59.7% of cases. The most common infectious agents were tick-borne encephalitis virus (TBEV) and varicella-zoster virus (VZV), while the most frequent non-infectious encephalitis was acute disseminated encephalomyelitis (ADEM). The analysis indicated that the introduction of new diagnostic methods did not significantly increase the likelihood of identifying the etiology. In conclusion, acute encephalitis is a complex condition requiring a multidisciplinary approach for diagnosis and treatment. Despite advance in diagnostics, a substantial amount of cases remain etiologically unresolved, underscoring the need for ongoing research and improvement in diagnostic strategies.