AbstractBacterial infections are a public health threat of increasing concern in medical care systems; hence, the search for novel strategies to lower the use of antibiotics and their harmful effects becomes imperative. Herein, the antimicrobial performance of four polyoxometalate (POM)‐stabilized gold nanoparticles (Au@POM) against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as Gram‐negative and Gram‐positive bacteria models, respectively, is studied. The bactericidal studies performed, both in planktonic and sessile forms, evidence the antimicrobial potential of these hybrid nanostructures with selectivity toward Gram‐negative species. In particular, the Au@GeMoTi composite with the novel [Ti₂(HGeMo₇O₂₈)₂]^10– POM capping ligand exhibits outstanding bactericidal efficiency with a minimum inhibitory concentration of just 3.12 µm for the E. coli strain, thus outperforming the other three Au@POM counterparts. GeMoTi represents the fourth example of a water‐soluble Ti^IV‐containing polyoxomolybdate, and among them, the first sandwich‐type structure having heteroatoms in high‐oxidation state. The evaluation of the bactericidal mechanisms of action points to the cell membrane hyperpolarization, disruption, and subsequent nucleotide leakage and the low cytotoxicity exerted on five different cell lines at antimicrobial doses demonstrates the antibiotic‐like character. These studies highlight the successful design and development of a new POM‐based nanomaterial able to eradicate Gram‐negative bacteria without damaging mammalian cells.