Significance Infection with Zika virus can cause severe consequences in a subset of the patient population. When infection occurs during pregnancy, congenital abnormalities can occur. Additionally, the onset of Guillain–Barré syndrome, encephalitis, and myelitis are associated with Zika virus infection. We have identified several small molecules with favorable clinical profiles, including the five-lipoxygenase–activating protein inhibitor, MK-591, and the tetracycline antibiotic, methacycline, as inhibitors of Zika virus infection, the latter of which reduced neurological deficits in a Zika virus mouse model. These compounds have the potential to be used as prophylactics or for the treatment of the neurological complications of Zika virus infection.