The main protease (Mpro) is a key enzyme responsible for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication that causes the spread of the global pandemic novel coronavirus (nCOVID-19) infection. In the present study, multiple computational approaches such as docking, long-range molecular dynamics (MD) simulations, and binding free-energy (BFE) estimation techniques were employed to investigate the mechanistic basis of the high-affinity inhibitors─GC-376, Calpain XII, and Calpain II (hereafter Calpain as Cal) from the literature─binding to Mpro. Redocking GC-376 and docking Cal XII and Cal II inhibitors to Mpro were able to reproduce all crucial interactions like the X-ray conformation. Subsequently, the apo (ligand-free) and three holo (ligand-bound) complexes were subjected to extensive MD simulations, which revealed that the ligand binding did not alter the overall Mpro structural features, whereas the heatmap analysis showed that the residues located in subsites S1 and S2, the catalytic dyad, and the 45TSEDMLN51 loop in Mpro exhibit a conformational deviation. Moreover, the BFE estimation method was used to elucidate the crucial thermodynamic properties, which revealed that Coulomb, solvation surface accessibility (Solv_SA), and lipophilic components contributed significant energies for complex formation. The decomposition of the total BFE to per-residue showed that H41, H163, M165, Q166, and Q189 residues contributed maximum energies. The overall results from the current investigation might be valuable for designing novel anti-Mpro inhibitors.