Periprosthetic joint infection (PJI) is a severe complication of total joint arthroplasty (TJA), leading to high rates of revision surgeries, long-term morbidity, and mortality. Conventional antibiotic treatments often suffer from limited bioavailability and systemic toxicity. This study explores a novel approach using vancomycin-loaded poly(lactic-co-glycolic) acid (PLGA) microparticles (VMP) formulated via a microfluidic double emulsion method for controlled, localized drug delivery for managing PJI. The PLGA microparticles were synthesized to achieve high loading capacity and sustained vancomycin release, aiming to maintain therapeutic intra-articular concentrations. In vitro characterization demonstrated optimal loading capacity (up to 28% w/w), morphology with a homogeneous particle size distribution (49–65 µm), and sustained release profiles over 8 weeks. In vivo efficacy was evaluated using a rat joint infection model, showing significant reductions in bacterial viability and enhanced bone healing compared to controls. Weight-bearing recovery assessments showed that VMP-treated rats regained functionality significantly earlier than controls (p < 0.05). Radiographic, histological, and immunofluorescent analyses confirmed reduced inflammation and improved bone integrity with VMP treatment. These findings suggest that microfluidic-synthesized PLGA microparticles provide a promising strategy for localized, controlled release of antibiotics, potentially helping the management of PJI and improving postsurgical outcomes. Future research should explore the long-term effects and scalability of clinical applications. This study lays the foundation for advancing controlled release systems in orthopedic postoperative care.