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Zika virus belongs to the Flavivirus family of RNA viruses, which include other important human pathogens such as dengue and West Nile virus. There are no approved antiviral drugs for these viruses. The highly conserved NS2B-NS3 protease of Flavivirus is essential for the replication of these viruses and it is therefore a drug target. Compound screen followed by medicinal chemistry optimization yielded a novel series of 2,6-disubstituted indole compounds that are potent inhibitors of Zika virus protease (ZVpro) with IC 50 values as low as 320 nM. The structure-activity relationships of these and related compounds are discussed. Enzyme kinetics studies show the inhibitor 66 most likely exhibited a non-competitive mode of inhibition. In addition, this series of ZVpro inhibitors also inhibit the NS2B-NS3 protease of dengue and West Nile virus with reduced potencies. The most potent compounds 66 and 67 strongly inhibited Zika virus replication in cells with EC 68 values of 1–3 μM. These compounds are novel pharmacological leads for further drug development targeting Zika virus. [Display omitted] • Compound screening identified indole-containing compounds 1 and 2 to be novel inhibitors of Zika virus NS2B-NS3 protease. • Medicinal chemistry optimization gave a significantly more potent inhibitor 66. • Compound 66 exhibited a strong antiviral activity against cellular replication of Zika virus. [ABSTRACT FROM AUTHOR]