The Hepatitis C Virus (HCV) NS3/4A protease is an attractive and established target for the treatment of Hepatitis C infection. Herein, we present an investigation of HCV NS3/4A inhibitors based on a sulfonamido-benzamide scaffold. We explored their interactions with HCV NS3/4A by molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations. The inhibitors all adopt similar molecular docking binding modes in the catalytic site of the protease that are stabilized by hydrogen bond interactions with G137 and the catalytic S139, which molecular dynamics simulations suggest to be important for potency and binding stability. Quantitative assessments of binding free energies from MM/PBSA correlate well with the experimental results, with a correlation coefficient R2 of 0.92. Binding free energy decomposition analyses were used to elucidate the differential contributions of Q41, F43, H57, R109, K136, G137, S138, S139, A156, M485, and Q526 with varying inhibitor structures. The importance of the Q41, F43, H57, R109, K136, S139, M485, and Q526 sidechain contributions was furthered confirmed by computational alanine scanning mutagenesis. The sidechains of K136 and S139 show particularly crucial contributions to the interactions with HCV NS3/4A. This extensive exploration of binding energies and interactions between these compounds and HCV NS3/4A at the atomic level should be of benefit to future antiviral drug design.