The misuse of antimicrobials has caused a remarkable increase of antibiotic-resistant bacteria. Developing novel antimicrobial agents with high activity and low rates of resistance development is in great demand yet challenging. In this context, we developed a novel cascaded AgNPs/nGOx/Apra nanocomposite for combinational antimicrobial therapy. Glucose oxidase nanocapsules (nGOx) in the nanocomposites can convert tissue glucose into H2O2, which in turn accelerates the erosion of AgNPs into Ag+, giving rise to a synergistic antibiotic/starving-like/metal ion therapeutic effect. An in vitro antimicrobial study of the nanocomposites demonstrated rapid bacterial killing, significant bacterial growth inhibition and broad antimicrobial spectra at a low antibiotic dose. More importantly, topical and microneedle-assisted deliveries of the nanocomposites resulted in rapid scarless skin recovery in both rabbit and mouse models. This nanocomposite platform opens up a new avenue for research and clinical applications to battle against microbial infections and reduce antibiotic-resistant rates.