An active recombinant Zika virus RNA-dependent RNA polymerase (RdRp) was prepared. An in vitro assay to measure its activity was developed. Nucleoside triphosphate (NTP) analogs that inhibit ZIKV RdRp are described. 2′-C-methylated NTPs inhibit ZIKV RdRp as expected. Unexpectedly, two structurally new active compounds were discovered among conformationally locked NTPs.