Infection of orthopedic implants is a growing clinical challenge to manage due to the proliferation of drug‐resistant bacterial strains. In this study, we aimed to investigate whether the treatment of implants with ceragenin‐90 (CSA‐90), a synthetic compound based on endogenous antibacterial peptides, could prevent infection in a novel rat model of periprosthetic joint infection (PJI) challenged with either local or systemic Staphylococcus aureus. A novel preclinical model of PJI was created using press‐fit porous titanium implants in the distal femur of male Wistar rats. Sterile implants were pre‐treated with 500 μg CSA‐90 in saline. S. aureus was applied either directly at the time of surgery or administered via tail vein injection immediately afterward. Animals were monitored daily for clinical and radiographic evidence of infection for a total of 6 weeks. Post‐study microbiological, radiographic, and histological analysis were performed to determine the incidence of PJI and assess osseointegration. CSA‐90 treated groups demonstrated a reduced rate of PJI as confirmed by deep tissue swab culture at the time of cull compared with untreated groups with both local (33% vs 100%; P =.009) and systemic (10% vs 90%; P <.0001) S. aureus inoculation. Median survival time also increased from 8 to 17 days and from 8 to 42 days, respectively. In conclusion, this study describes a novel preclinical model of local and hematogenous PJI using a porous metal implant. CSA‐90 reduced the incidence of PJI in this model supporting its further development as an antimicrobial coating for orthopedic implants. [ABSTRACT FROM AUTHOR]