A periprosthetic joint infection (PJI) with methicillin-resistant Staphylococcus aureus (MRSA) is a catastrophic deep joint infection for patients who have had joint replacement surgery. To efficiently eradicate the MRSA, curcumin-upconversion nanoparticles (curcumin-UCNPs) were synthesized by binding the curcumin onto UCNPs, which could produce singlet oxygen under near infrared (NIR) irradiation. Dual antibacterial behavior induced by the curcumin-UCNP itself and induced by photodynamic therapy were demonstrated. Nearly 100% MRSA was eradicated using curcumin-UCNPs under the NIR irradiation because of the dual antibacterial behavior in vitro. Furthermore, a MRSA-induced PJI model was constructed using Sprague Dawley rats. The NIR could penetrate the rats' knee joint tissue well and activated the curcumin-UCNPs to perform photodynamic therapy, which exhibited a good antibacterial effect in the deep joint tissue (1 cm) and about 80% of MRSA was eradicated in vivo. Blood tests and histopathological examinations revealed that the inflammation was also significantly relieved because of the eradication of MRSA in the curcumin-UCNPs-NIR group. Compared with traditional treatments, this research may provide a new therapy for PJI.