Hepatitis C virus (HCV) is a major threat to global public health causing 700,000 deaths annually. HCV has high genotypic diversity with eight recognized genotypes (G 1-8) and ~67 subtypes. With the advent of direct-acting antivirals (DAAs), rapid progress has been made towards treating HCV in the last decade. However, despite significant efforts in drug development, resistant mutations alongside genotypic variation challenge the efficacy of approved drugs. Furthermore, since most of the approved antivirals are specific to G1, a reduced efficacy is observed against other genotypes that are prevalent in developing countries including Pakistan. In this work we have mapped sequence variation within HCV G3a protease, NS3/4A, a significant drug target. We report drug resistant mutations within the interacting residues (D168Q, T178Q, V183S and N518S) at NS3/4A binding site responsible for drug resistance in HCVG3a. We have applied several in silico methods from structure modeling to pharmacophorebased virtual screening (PBVS) towards identifying novel compounds targeting HCV NS3/4A G3a. We report five-top hit compounds (C1–C5) indicating strong hydrogen bond interactions contributing towards stable compound-receptor complexes. These compounds not only exhibit strong binding affinity scores (-8.0 to -6.6 kcal/mol) in comparison with the known NS3/4A inhibitors (-7.0 to - 3.7 kcal/mol), but also bind to the reportedly mutated interacting residues (Q168, Q178, S183 and S518) in G3a, highlighting their potential towards HCV drug development.