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Powassan virus (POWV) is an emerging tick-borne flavivirus endemic to the northern and northeastern United States. Severe human POWV infection is characterized by fatal encephalitis in 10% of patients and long-term neurological sequelae in 50% of survivors. Little is known about humoral immunity to POWV, and there are currently no licensed vaccines or therapeutics available for treatment. We have generated a panel of 23 murine antibodies against POWV that separate into six epitope groups based on competitive binding. Two of the groups target domain III of the viral envelope protein; mapping by alanine scanning mutagenesis places their epitopes on the A-strand and CC′ loop of domain III, respectively. These DIII-specific mAbs display potent neutralization in vitro and robust protection in a mouse model of POWV infection. X-ray crystallographic analysis reveals that POWV-80, a CC′ loop antibody …