Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PAN) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PAN endonuclease inhibition, a fragment-based drug development campaign was pursued. Guided by coordination chemistry and structure-based drug design, MBP scaffolds were elaborated to improve activity and selectivity. Structure-activity relationships were established and used to generate inhibitors of influenza endonuclease with tight-binding affinities. The activity of these inhibitors was analyzed using a fluorescence-quenching-based nuclease activity assay, and binding was validated using differential scanning fluorometry. Lead compounds were found to be highly selective for PAN endonuclease against several related dinuclear and mononuclear metalloenzymes. Combining principles of bioinorganic and medicinal chemistry in this study has resulted in some of the most active in vitro influenza PAN endonuclease inhibitors with high ligand efficiencies.