Powassan encephalitis is a rare but severe disease caused by infection with Powassan virus (POWV). It is a tick-borne Flavivirus (family Flaviviridae) having single stranded Ribonucleic Acid (RNA) which is positive sense in nature. The virus has highest case-fatality rates and is associated with a very high incidence of severe neurologic sequelae. Humans contract POWV infection accidentally when they are exposed to areas where the virus, arthropod vector (an Ixodid tick) and the vertebrate natural hosts coexist. Reported incubation periods for Powassan virus range from 8 to 34 days. The disease is associated with a reactive inflammatory cellular infiltrate (chronic) of lymphocytes and macrophages that include the abundance of perivascular inflammatory cells and multiple foci of parenchymal cells in grey matter. Basically two diagnostic approaches are considered. First one is the direct detection of the virus or viral RNA in the initial (viremic) phase of infection by virus isolation in mammalian cell culture or by reverse transcriptase polymerase chain reaction (RT-PCR). Second is the indirect detection of specific immunoglobulins (IgM and IgG antibodies) with serological methods such as Enzyme Linked Immunosorbent Assay (ELISA); Immunofluorescence Assay (IFA) or Neutralization Tests (NTs). Phylogenetic analysis is important for genogrouping of the virus. Oligomers targeting specific locations in the RNA genome of the flavivirus have been used at present for successful suppression of viral gene expression. Strict hygienic and biosafety measures including tick control is pre-requisite for prevention of disease. The present review will give an insight to the details of disease caused by this arbovirus that may often prove fatal, its epidemiology, diagnosis, prevention and control measures to be adopted.