<p>The increasing number of joint replacement surgeries has led to an increase in periprosthetic joint infections (PJI). Chronic PJI caused by <i>Staphylococcus epidermidis</i> is very common and challenging to treat, prompting interest in bacteriophage therapy. Preclinical studies are essential for optimizing phage administration routes and dosages. Here, phage replication and bacterial growth inhibition using phage and vancomycin were first assessed in vitro. Then, chronic PJI was induced in mice using biofilm-coated titanium implants inoculated with <i>S. epidermidis</i> COB-SE3 to evaluate the efficacy of phage COP-80B and vancomycin therapy. Mice received one intra-articular and two intraperitoneal phage doses over three days, along with vancomycin administered twice daily for five days. Four weeks after implantation, we quantified and compared bacterial loads in periarticular tissues and implants across four groups: untreated controls, phage monotherapy, vancomycin monotherapy, and phage-vancomycin combination. Infection persistence was lower than expected, limiting the ability to detect treatment effects and assess therapeutic efficacy in this low-virulence model. Intra-articular administration of 10¹⁰ PFU of COP-80B did not alter plasma alanine aminotransferase levels, indicating no hepatotoxicity. Bacterial isolates remained susceptible to both phage and vancomycin, while phage-neutralizing antibodies developed during treatment. Overall, this study evaluates phage-vancomycin therapy while also contributing a murine model that advances methodological development for chronic <i>S. epidermidis</i> PJI research, with additional refinement of infection kinetics needed to reliably assess therapeutic efficacy.</p>