The development of modular strategies for programming self-assembled supramolecular architectures with distinct structural and functional features is of immense scientific interest. We reported on the intrinsic antibacterial capability of anionic amphiphilic gold nanoclusters (GNCs) capped by para-mercaptobenzoic acid, which was closely related to the protonation level of terminal carboxylate groups. By using of the metal−ligand coordination-driven and solvent evaporation-induced self-assembly, we constructed GNCs-based mixed-metal metal−organic network (MM-MON) films on titanium disks as antibacterial nanocoatings. Taking the reasonable utilization of tetravalent metal ions M 4+ (Ti, Zr, Hf; hard Lewis acid) and bactericidal divalent metal ions M 2+ (Cu, Zn; borderline acid) co-incorporated metal−carboxylate coordination bonds, the MM-MON films exhibited superior stability due to the robust M 4+ −O bonds and M 2+ releasing behavior resulting from the labile M 2+ −O coordinating. Together, the MM-MON films integrated the bacteria-responsive character of GNCs, exceptional chemical stability, and greatly enhanced antibacterial activity, ultimately killing adherent bacteria and initiating a self-defensive function. In a rat model for subcutaneous implant-associated infection, the MM-MON nanocoating showed an approximately 2 and 1 log lower multidrugresistant Staphylococcus aureus implant and tissue colonization, respectively. The generalizable modular strategy of the GNC− metal networks is amenable to facilitate the functionalization of metal surfaces for combating implant-associated infections.