Since 2007, repeated outbreaks of Zika virus (ZIKV) have affected millions of people worldwide and created a global health concern with major complications like microcephaly and Guillain Barre’s syndrome. To date, there is not a single Zika-specific licensed drug present in the market. However, in recent months, several antiviral molecules have been screened against ZIKV. Among those, (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, has shown great virucidal potential against flaviviruses including ZIKV. The mechanistic understanding of EGCG-targeting viral proteins is not yet entirely deciphered except that little is known about its interaction with viral envelope protein and viral protease. We designed our current study to find inhibitory actions of EGCG against ZIKV NS3 helicase. NS3 helicase performs a significant role in viral replication by unwinding RNA after hydrolyzing NTP. We employed molecular docking and simulation approach and found significant interactions at the ATPase site and also at the RNA binding site. Further, the enzymatic assay has shown significant inhibition of NTPase activity with an IC value of 295.7 nM and Ki of 0.387 ± 0.034 μM. Our study suggests the possibility that EGCG could be considered as a prime backbone molecule for further broad-spectrum inhibitor development against ZIKV and other flaviviruses.Copyright © 2020 American Chemical Society.