Methicillin-resistant Staphylococcus aureus (MRSA) has become a rising clinical problem as its occurrence has increased due to the overuse and misuse of antibiotics. In this work, upconversion nanoparticles@AgBiS₂ core–shell were produced with enhanced photothermal transformation efficiency and ability to produce reactive oxygen species for synergistic photodynamic photothermal and photodynamic antibacterial performance. The nanoparticles exhibit good antibacterial effects in vitro and satisfactory therapeutic performance on healing MRSA-infected wounds in vivo experiments. RNA-sequencing technique has been used to investigate and reveal that photothermal–photodynamic therapy using the nanoparticles can interfere with metabolic processes such as galactose metabolism in MRSA bacteria, destroy the transport system on the surface of MRSA, and affect quorum sensing to hinder the formation of biofilms to achieve effective antibacterial efficacy. It was demonstrated that this work presents an alternative near-infrared photoactive multimodal nanostructure for antibacterial applications.