Rifampin is a crucial antibiotic in the management of prosthetic joint infections (PJI), particularly due to its effectiveness against staphylococcal bacteria and its ability to penetrate and disrupt biofilms. This review evaluates rifampin's role by examining its mechanism of action, clinical efficacy, and integration into treatment regimens based on recent evidence and guidelines. Rifampin's synergistic effects with other antibiotics, such as β-lactams and vancomycin, enhance bacterial eradication, and some evidence shows that it improves patient outcomes. However, evidence supporting its use is limited by the scarcity of robust human clinical trials, and challenges such as potential drug interactions and resistance development necessitate careful management. Ongoing research is needed to refine its use and address existing limitations in clinical practice.