Multidrug resistant (MDR) bacterial infections, particularly those involving methicillin-resistant Staphylococcus aureus (MRSA), pose a grave threat to global population health, necessitating novel therapeutic approaches capable of circumventing existing resistance mechanisms. Biomimetic enzymes, which generate bactericidal reactive oxygen species (ROS) by mimicking natural enzyme activity, represent a highly promising solution. This study reports a straightforward one-step synthesis method for vanadium dioxide (VO₂) nanoparticles, which function as potent biomimetic enzymes exhibiting both oxidase-like and peroxidase-like activities. When combined with near-infrared laser irradiation (808 nm, 1 W/cm²) for photothermal therapy (PTT), these VO₂ nanoparticles not only mediate local hyperthermia with a photothermal conversion rate of up to 36.9%, but also significantly enhance ROS generation through biomimetic catalysis. This achieves potent synergistic effects between photothermal therapy and chemodynamic therapy (CDT). This combined therapy exhibits potent antibacterial activity against suspended methicillin-resistant Staphylococcus aureus (MRSA) and effectively disrupts preformed biofilms. Furthermore, in a subcutaneous abscess mouse model, VO₂-mediated PTT-CDT treatment efficiently eradicated bacteria, alleviated local inflammation, promoted tissue repair and angiogenesis. In summary, this readily synthesised VO₂ nanozyme system offers an efficient and translatable therapeutic strategy for tackling challenging multidrug-resistant bacterial infections.