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-characterised 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. Interestingly, antiviral effects were similar regardless of whether these compounds were added before, during or after viral infection, while subgenomic replicon experiments revealed significant antiviral effects against viral RNA replication. Since Huh-7.5 cells and HTR-8 cells lack detectable expression of estrogen receptors-α and -β (ER-α and ER-α), these compounds appear to act in a manner that is independent of their known effects on estrogen receptor signalling and may disrupt multiple aspects of the viral life cycle, including viral RNA replication. Taken together, Quinestrol, Raloxifene hydrochloride and structurally related analogues warrant further investigation as potential therapeutics for treatment of flavivirus infections.