Antibacterial nanomaterials have attracted growing interest for bacterial infection therapy. However, most nanomaterials eliminate bacteria either physically or chemically, which hampers their efficacy when dealing with multidrug-resistant bacteria. To overcome this, we integrated copper sulfide (CuS) nanoparticles with active graphene oxide nanosheets (GO NSs) to synthesize a superior nanocomposite (CuS/GO NC) that acts both physically and chemically on the bacteria. CuS/GO NC was produced using a facile hydrothermal method, whereby the CuS nanoparticles grew and were uniformly dispersed on the GO NSs in situ. We found that the CuS/GO NC possesses a unique needle-like morphology that physically damages the bacterial cell membrane. CuS/GO NC also exhibits high oxidase- and peroxidase-like activity, ensuring efficient generation of the reactive oxygen species center dot OH from H2O2, which kills bacteria chemically. These features endow the CuS/GO NC with excellent antibacterial capabilities to kill multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) with only a single dose. Additionally, it was found that the CuS/GO NC accelerated the healing of infected wounds in vivo owing to its good biocompatibility as well as facilitation of cell migration and collagen secretion. This study provides a new strategy to combine the physical and chemical antibacterial modes of nanomaterials to develop more effective therapies to combat multidrug-resistant bacterial infections.