St. Louis encephalitis virus (SLEV) was first recognized in 1933 and caused a major encephalitis epidemic with 1095 clinical cases and 201 deaths in St. Louis, Missouri. According to the median values from 2014 to 2018, the percentage of neuroinvasion by SLEV was 62% and the fatality rate was 9% in the United States. The clinical symptoms of SLEV infection include neurological abnormalities such as memory loss, disorientation, and meningoencephalitis. Till now, specific treatments including vaccine and drug are unavailable for SLEV infection. It is of particular importance to get prepared for SLEV infection, especially given the currently raging global COVID-19 epidemic.