Multidrug resistance represents a growing threat to human beings, and alternative antimicrobial regimens to conventional antibiotic paradigms are being extensively searched to fight against multidrug-resistant bacteria (MDRB). Although the antimicrobial potency of silver nanomaterials (AgNMs) has been previously elaborated, their efficacy against MDRB still remains to be strengthened. Here, our data revealed that small-sized silver nanoclusters (AgNCs) are superior to conventional silver nanoparticles (AgNPs) as robust antimicrobials against multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa). The core structure and surface ligands of AgNCs are crucial for the outstanding antibacterial activity of AgNCs. On the one hand, due to the presence of amphiphilic ligands, AgNCs are relatively prone to associate with the cell membrane and partake in endocytosis with targeted bacterial cells. Molecular dynamics simulations also corroborated this finding. On the other hand, the nanocluster structure of AgNCs led to strong peroxidase-like activity associated with massive production of reactive oxygen species (ROS), which contributes to their overall bactericidal potency. These outstanding features of AgNCs result in elevated bacterial killing efficacy by impairing the cell wall/membrane, promoting oxidative stress and attenuating pivotal cellular processes, e.g., ATP synthesis. Notably, AgNCs manifested great efficacy in treating P. aeruginosa-generated pneumonia in mice and increased the survival of infected animals, as well as exhibited excellent biocompatibility. Taken together, the results of this study pinpoint the great promise of AgNCs as new alternative therapeutics against MDR P. aeruginosa. Biomaterials: A silver bullet against drug-resistant bacteriaA silver nanomaterial that can destroy drug-resistant bacteria has been developed by researchers in China. The rise of antibiotic-resistant bacteria is a major source of concern in global health. Silver has long been known to have antibacterial properties, and so scientists are returning to it as a possible agent to combat these multidrug-resistant bacteria. While silver nanoparticles have previously been shown to have good antibacterial activity, a team led by Nanfeng Zheng, Xiamen University, and Sijin Liu, Chinese Academy of Sciences, Beijing, have shown that small clusters of silver particles are even better. The researchers determined the optimal size, structure and surface properties of antibacterial nanosilver clusters. They used their nanoclusters to treat pneumonia in mice caused by the multidrug-resistant bacteria Pseudomonas aeruginosa, increasing their survival rates. Our findings unearth the great importance of the size, core structure, and surface ligands in dictating the antibacterial activity of silver nanoclusters (AgNCs). Owing to the presence of amphiphilic ligands, AgNCs are more prone to adsorb the membrane and following endocytosis towards targeted bacterial cells, associated with membrane damage, as reflected by reinforced release of malondialdehyde (MDA). AgNCs bear strong peroxidase-like activity, coupled to massive production of reactive oxygen species (ROS). Altogether, these outstanding features of AgNCs resultantly elevated the bacteria-killing efficacy through impairing cell wall/membrane, promoting oxidative stress and attenuating pivotal cellular processes, e.g., ATP synthesis. org/1999/xlink" xlink:href="41427_2020_239_Figa_HTML.png"></graphic