Flavivirus NS5 RNA-dependent RNA polymerase (RdRp) is an important drug target. Whilst a number of allosteric inhibitors have been described for Hepatitis C virus RdRp, few have been described for DENV RdRp. In addition, compound screening campaigns have not yielded suitable leads for this enzyme. Using fragment-based screening via X-ray crystallography, we identified a biphenyl acetic acid fragment that binds to a novel pocket of the dengue virus (DENV) RdRp, in the thumb/palm interface, close to its active site (termed “N pocket”). Structure-guided optimization yielded nanomolar inhibitors of the RdRp de novo initiation activity, with low micromolar EC50 in DENV cell-based assays. Compound-resistant DENV replicons exhibited amino acid mutations that mapped to the N pocket. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors and provides a significant opportunity for rational design of novel therapeutics against this proven antiviral target.