Recently emerging graphene-based 2D nanoplatforms with multiple therapeutic modalities provide enormous opportunities to combat pathogenic bacterial infections. However, because these materials suffer from complicated synthesis, massive dosage requirements, and abundant nonlocalized heat, much more simplified, tunable, and localized eradication approaches are urgently required. Herein, we report on the fabrication of the metal–organic-framework (MOF)-derived 2D carbon nanosheets (2D-CNs) with phase-to-size transformation and localized bacterial eradication capabilities for augmented anti-infective therapy. The MOF-derived, ZnO-doped carbon on graphene (ZnO@G) is first synthesized and then anchored with phase transformable thermally responsive brushes (TRB) by in situ polymerization to yield the TRB-ZnO@G. The TRB-ZnO@Gexhibits flexible 2D nanostructures, high photothermal activities, sustained Zn2+ ions release, and ON–OFF switchable phase-to-size transformation abilities. Notably, the near-infrared-triggered formation of TRB-ZnO@G-bacteria aggregations enables localized massive Zn2+ ions penetration, physical cutting, and hyperthermia killing, which synergistically enhance the disruption of bacterial membranes and intracellular substances. The obtained novel 2D-CNs not only present robust and localized multiple bacterial eradication capabilities with nearly 100% bactericidal efficiency at low concentrations but also possess rapid and safe skin wound disinfection via a short-time photothermal treatment without damaging normal skin tissues or causing accumulative toxicities, thus presenting great potential for broad-spectrum eradication of pathogenic bacteria.