To identify a new protective or therapeutic intervention for hepatitis C virus (HCV) infection, we performed efficient structure-based virtual screening to identify novel inhibitory agents for HCV. To this end, we selected NS5B, an RNA-dependent RNA polymerase (RdRp), as the target for the treatment of HCV infection. To decipher the dockable nature of various RdRp X-ray crystals, we docked the crystal ligand (inhibitor) to the crystal receptor (enzyme). The accuracy of regeneration of the crystal pose indicates the amenability of the RdRp binding pocket for structure-based virtual screening. We also utilized a consensus scoring scheme to reduce false positives, thereby ensuring efficient virtual screening. In this study, each molecule that ranked in the top 1% among all screening molecules gained 1 consensus point in a scoring function. Thus, after virtual screening of 57,177 chemicals from the Maybridge Screening collection, 14 molecules gained 8 points across 11 scoring functions. One of them, an isoxazole, showed significant dose-dependent inhibition of HCV RdRp activity and replication. In this study, we have developed a structure-based virtual screening method using HCV RdRp for efficient identification of novel inhibitors.