Today, prosthetic joint infection (PJI) is still a relatively rare but devastating complication following total hip and/or knee arthroplasty. The treatment of PJI is difficult due to a number of obstacles, such as microbial drug resistance, biofilm protection, and insufficient immune activity, which dramatically diminish the cure rate of PJI to <50%. To efficiently eradicate the bacteria hiding in the implant, photo-chemical joint antibacterial therapeutics based on indocyanine green (ICG) and rifampicin (RIF) co-loaded PLGA nanoparticles (IRPNPs) were developed in this study. The IRPNPs were first characterized as a spherical nanostructure with a size of 266 ± 18.2 nm and a surface charge of -28 ± 1.6 mV. In comparison with freely dissolved ICG, the IRPNPs may confer enhanced thermal stability to the encapsulated ICG and are able to provide a comparable hyperthermic effect and increased production of singlet oxygen under 808 nm near infrared (NIR) exposure with an intensity of 6 W cm-2. Based on the spectrophotometric analysis, the IRPNPs with ≥20-/3.52 μM ICG/RIF were able to provide remarkable antibiofilm and antimicrobial effects against bacteria in a porous silicon bead upon NIR exposure in vitro. Through the analysis of the microbial population index in an animal study, ≥70% Staphylococcus capitis subsp. urealyticus grown in a porous silicon bead in vivo can be successfully eliminated without organ damage or inflammatory lesions around the implant by using IRPNPs + NIR irradiation every 72 h for 9 days. The resulting bactericidal efficacy was approximately three-fold higher than that resulting from using an equal amount of free RIF alone. Taken together, we anticipate that IRPNP-mediated photochemotherapy can serve as a feasible antibacterial approach for PJI treatment in the clinic.