Hepatitis C virus (HCV) NS3/4A protease is an important and attractive target for anti-HCV drug development and discovery. Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease. However, the emergence of resistance to these two inhibitors reduced the effectiveness of vaniprevir and MK-5172 against viral replication. Among the drug resistance mutations, three single-site mutations at residues Arg155, Ala156, and Asp168 in NS3/4A protease are especially important due to their resistance to nearly all inhibitors in clinical development. A detailed understanding of drug resistance mechanism to vaniprevir and MK-5172 is therefore very crucial for the design of novel potent agents targeting viral variants. In this work, molecular dynamics (MD) simulation, binding free energy calculation, free energy decomposition, residue interaction network (RIN), and substrate envelope analysis were used to study the detailed drug resistance mechanism of the three mutants R155K, A156T, and D168A to vaniprevir and MK-5172. MD simulation was used to investigate the binding mode for these two inhibitors to wild-type and resistant mutants of HCV NS3/4A protease. Binding free energy calculation and free energy decomposition analysis reveal that drug resistance mutations reduced the interactions between the active site residues and substituent in the P2 to P4 linker of vaniprevir and MK-5172. Furthermore, RIN and substrate envelope analysis indicate that the studied mutations of the residues are located outside the substrate (4B5A) binding site and selectively decrease the affinity of inhibitors but not the activity of the enzyme and consequently help NS3/4A protease escape from the effect of the inhibitors without influencing the affinity of substrate binding. These findings can provide useful information for understanding the drug resistance mechanism against vaniprevir and MK-5172. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.