Thousands of people worldwide have been infected with Japanese encephalitis virus, which is spreading year after year. JEV is endemic mainly in Southeast Asia with 69,000 cases every year. The mortality rate associated with JE infection is around 25–30%, whereas patients who survive after infection may suffer from severe neurological disabilities throughout their life. The infected individual may develop symptoms such as rapid onset of high fever, headache, vomiting, paralysis, movement disorders and seizures. For the time being, there is no FDA-approved antiviral therapy for JEV. Although a few randomized clinical trials have been conducted to test the efficacy of dexamethasone, minocycline, ribavirin, intravenous immunoglobulin (IVIG) and IFN-α2a against JEV infection, none of these studies have showed a measurable advantage on any clinical outcome measure. However, vaccines are available, but despite vaccination, the annual cases of JEV do not decrease significantly in India as well as Southeast Asia. Host-directed therapy (HDT) that hampers host cell processes, boosts immune responses, minimises excessive inflammation or balances host reactivity at the site of infection shows tremendous potential for the selective and symptomatic treatment during viral infections. In this chapter, we discuss the potential targets such as envelope protein, non-structural protein 1, JEV protease, helicase/nucleoside triphosphatase and RNA-dependent RNA polymerase and various host targets for anti-JEV drug design, list of various repurposed drugs, medicinal plants and their derivatives which have been tested against JEV infection in cell culture, animal models and clinical trials.