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Zika virus (ZIKV) is a mosquito-borne virus that has risen to prominence as a significant threat to public health in the recent decade. Since its re-emergence in 2007, ZIKV has spread at an alarming rate and has since become endemic to multiple regions around the world. Infections are primarily asymptomatic, however the virus has become associated with the development of severe neurological complications such as Guillain-Barré syndrome (GBS) and congenital microcephaly. At present, there are currently no approved antivirals for ZIKV infections. In this study, we utilised a phenotype-based screening platform to perform a high-throughput screen on a 1172-compound US FDA-approved drug library to identify potential novel inhibitors against ZIKV. Candesartan cilexetil, an angiotensin II receptor inhibitor, displayed potent inhibition effects against ZIKV and subsequent downstream time-course studies revealed that it targets a post-entry stage(s) of the ZIKV replication cycle. Moreover, candesartan cilexetil also inhibited viral RNA production and viral protein synthesis. Candesartan cilexetil also exhibited antiviral effects against Dengue virus serotype-2 (DENV2), Kunjin virus (KUNV) and Chikungunya virus (CHIKV), indicating that its antiviral properties may not be restricted to ZIKV. Our study has demonstrated for the first time the potential application of candesartan cilexetil as an antiviral., (Copyright © 2019 Elsevier B.V. All rights reserved.)