The main protease (M) stands as a pivotal enzyme crucial for coronavirus replication, thus serving as a prime target for coronavirus drug discovery endeavors. Nirmatrelvir (PF-07321332), an antiviral compound developed by Pfizer, has been engineered to selectively inhibit the M of SARS-CoV-2 by directly binding to its catalytic cysteine residue (Cys145). In a bid to scrutinize the expansive inhibitory spectrum of PF-07321332 against a gamut of human pathogenic coronaviruses, we undertook an exhaustive investigation leveraging molecular dynamics (MD) simulations in conjunction with binding free energy (BFE) calculations. Molecular dockings of PF-07321332 with the Ms of seven human coronaviruses yielded their optimal binding modes (complexes), subsequently subjected to rigorous MD simulations and BFE assessments. The results of MD simulations indicated that PF-07321332 can remain stable in the substrate-binding cavity of all the seven human coronaviruses Ms. A detailed comparison of BFE components revealed that intermolecular van der Waals (vdW) interactions play a significantly more crucial role in maintaining association and determining the high binding affinity than intermolecular electrostatic interactions. Analyses of residue BFE decomposition reveals Cys145 as a pivotalt amino acid, positively influencing the stable binding between Ms and inhibitor. These finding imply that PF-07321332 has the potential to be an effective anti-coronavirus inhibitor and also provide insights into inhibitor optimization and drug design strategies against human coronavirus.