The main protease (Mpro) is an essential enzyme for coronavirus replication and is therefore a target for coronavirus drug discovery. Nirmatrelvir (PF-07321332) is an antiviral ¬¬medication developed by Pfizer, which is targeted against the Mpro of SARS-CoV-2 as a covalent inhibitor that directly binds to the catalytic cysteine (Cys145). However, whether it has inhibitory effects on other human pathogenic coronaviruses has not been reported. To explore the broad-spectrum inhibitory activity of Nirmatrelvir against human pathogenic coronaviruses, we performed a comprehensive study using molecular dynamics (MD) simulations combined with binding free energy (BFE) calculations. The molecular dockings between PF-07321332 and the seven human coronaviruse Mpros, and provided their best matching binding modes (complexes), which were futher subjected to MD simulations and BFE calculations. The results of MD simulations indicated that PF-07321332 can remain stable in the substrate-binding cavity of all the seven human coronaviru Mpros. A detailed comparison of BFE components revealed that intermolecular van der Waals (vdW) interactions are much more important in maintaining association and determining high affinity than intermolecular electrostatic interactions. Analyses of residue BFE decomposition showed that Cys was the key amino acid that positively contributed to the stable combination of Mpro and inhibitor. We can infer that PF-07321332 has the potential to become a broad-spectru