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Zika virus (ZIKV) is rapidly spreading throughout the Americas and is associated with significant fetal complications, most notably microcephaly. Treatment with polyclonal antibodies for pregnant women at risk of ZIKV-related complications could be a safe alternative to vaccination. We found that large quantities of human polyclonal antibodies could be rapidly produced in transchromosomal bovines (TcB) and successfully used to protect mice from lethal infection. Additionally, antibody treatment eliminated ZIKV induced tissue damage in immunologically privileged sites such as the brain and testes and protected against testicular atrophy. These data indicate that rapid development and deployment of human polyclonal antibodies could be a viable countermeasure against ZIKV.Transchromosomal Bovine (TcB) were developed to produce human polyclonal antibody.Vaccinated TcB produce high-titer neutralizing antibody to Zika virus.Human ZIKV-TcB antibodies prevent lethal disease in two mouse models.ZIKV-TcB antibodies prevent tissue damage and testicular atrophy in mice.Delayed treatment results in significant protection from lethal ZIKV infection.