SARS-CoV-2 main protease (Mpro, 3CLpro, PDB ID: 6LU7) cleaves viral polyproteins pp1a and pp1ab at 11 conserved recognition sites, releasing the non-structural proteins needed for replication–transcription complex assembly. Its catalytic HIS41-CYS145 dyad lacks a close human homolog, providing Mpro with a reasonable selectivity window as a drug target. Four approved antifungal azoles—posaconazole, itraconazole, fluconazole, and ketoconazole—were evaluated in this study as candidate non-covalent inhibitors against the 6LU7 crystal structure (2.16 Å) using AutoDock Vina v1.2.5 under rigid-receptor conditions. GC-376, a non-covalent Mpro inhibitor with published IC₅₀ data, was docked under identical conditions and served as the primary scoring reference (ΔG = −6.763 kcal/mol). Nirmatrelvir was retained solely for the mechanistic context; rigid non-covalent docking cannot model its CYS145-alkylating mechanism. Posaconazole returned the strongest predicted affinity (−8.288 kcal/mol), followed by itraconazole (−8.095 kcal/mol), fluconazole (−5.068 kcal/mol), nirmatrelvir (−4.370 kcal/mol), and ketoconazole (−3.769 kcal/mol). Posaconazole occupied the HIS41-CYS145 catalytic cleft with predicted contacts at MET49 (~3.8 Å), MET165 (~4.1 Å), GLU166 (~3.3 Å), and the catalytic dyad residues HIS41 (~3.2 Å) and CYS145 (~3.5 Å). These distances were estimated from a rigid-receptor protocol and carry inherent coordinate uncertainty; they are not experimentally validated geometries. Posaconazole and itraconazole both carry multiple Lipinski violations, elevated lipophilicity (LogP > 4.5), predicted hERG II inhibition, and hepatotoxicity risk. Fluconazole showed a clean absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile, with weaker predicted binding (−5.068 kcal/mol). No antiviral activity was claimed. Molecular dynamics simulation, binding free energy calculation, and in vitro Mpro inhibition assays are required before any biological inference can be drawn.