Methods of treating or preventing a Flavivirus infection in a subject are provided. The methods comprise administering to the subject a therapeutically effective amount of a Flavivirus inhibitor, e.g., a Flavivirus protease inhibitor. These methods are useful in treating and/or preventing Flavivirus infections such as, for example, West Nile Virus, Dengue Virus, and Japanese Encephalitis Virus. Methods of inhibiting a Flavivirus protease in a cell are also provided.