Acute encephalitis syndrome (AES) is the clinical manifestation, which includes symptoms such as convulsions, sensorium alterations, and behavioral changes. The Japanese encephalitis virus (JEV) accounts for 5–35% of AES incidence in India. The disease can cause significant morbidity and mortality and typically affects children and young adults. Japanese encephalitis (JE) continues to be one of the world’s most serious infections with no definitive treatment. JEV is the most common cause of viral encephalitis in several Asian nations, with a case fatality rate of approximately 30%, while 30–50% of survivors develop permanent neurologic or mental sequelae. Genotype V of JEV was found in human samples for the first time, denoting significant virulence and the potential for viral encephalitis. In most cases, the incubation time is between 5 and 15 days. Human viremia is mild and short-lived, occurring only in the early stages of the illness. JEV transmission is a danger in 24 countries in the WHO Western Pacific areas and Southeast Asia affecting about three billion people. Culex tritaeniorhynchus is responsible for the transmission of JEV through infected mosquitoes bites to humans. So far, there is no FDA-approved antiviral therapy for JEV. However, various drugs are repurposed and tested in cell culture as well as animal models against JEV.