Antibiotic is one of the greatest discoveries in human history. It has drastically promoted modern medicine and extended the average human lifespan. However, antibiotic resistance has become a global crisis today and the development of novel antibiotics is highly demanded. The traditional antibiotics not only kill the pathogen but also damage the resident microbiome in the human body, thus promoting antibiotic resistance and elevating the risk of patients for new infection. Here, we fabricated an activable metal-phenolic network nano-antibiotics (PEG-P18-Ag NPs) that can be selectively activated on the site of infection, thus presumably avoiding their impacts on the resident microbiome. We showed that PEG-P18-Ag NPs per se do not have any antibacterial activity. However, upon activation by the ultrasound, they triggered the generation of reactive oxygen species. Consequently, PEG-P18-Ag NPs remarkably killed various multi-drug resistant bacteria and established biofilms in vitro and in vivo. By RNA sequencing, we revealed that activated PEG-P18-Ag NPs produced a profound damaging effect on the bacteria. Collectively, we provided a novel approach for the new generation of antibiotics that selectively target infected bacteria. [Figure not available: see fulltext.].