Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2M^pro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2M^pro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC₅₀, for SC2M^pro in the 8–34 μM range, the IC₅₀ values are ca. 100 nM for Zn(NO₃)₂ which are further enhanced in Zn–L combinations (59–97 nM). Isolation of the Zn(L)₂ binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2M^pro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn–L combinations orient so as to permit dative bonding of Zn(L)⁺ to basic active site residues.