Flaviviruses such as Zika virus (ZIKV), dengue virus (DENV) and West Nile virus (WNV) are major global pathogens for which safe and effective antiviral therapies are not currently available. To identify antiviral small molecules with well-characterized safety and bioavailability profiles we screened a library of ~2,900 approved drugs and pharmacologically active compounds for inhibitors of ZIKV infection using a high-throughput cell-based immunofluorescence assay. Interestingly, estrogen receptor modulators Quinestrol and Raloxifene hydrochloride were amongst 15 compounds that significantly inhibited ZIKV infection in repeat screens. Subsequent validation studies revealed that these drugs effectively inhibit ZIKV, DENV and WNV (Kunjin strain) infection at low micromolar concentrations with minimal cytotoxicity in Huh-7.5 hepatoma cells and HTR-8 placental trophoblast cells. Since pre-treatment of cells with these drugs was associated with more potent antiviral effects and these cells lack detectable expression of estrogen receptors, these compounds appear to inhibit early events during flavivirus infection in a manner that is independent of their known effects on estrogen receptor signaling. Taken together, Quinestrol, Raloxifene hydrochloride and structurally related analogs warrant further investigation as potential therapeutics for treatment of flavivirus infections.