Introduction: Vancomycin is a widely used antibiotic in Outpatient Parenteral Antimicrobial Therapy (OPAT) services. The objective of this systematic review was to evaluate the published literature on the efficacy and safety outcomes of outpatient vancomycin therapy. Methods: A systematic search was performed in Embase, Medline ALL, the Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials from database inception until 20 March 2026. Both randomized controlled trials and non-randomized studies published in peer-reviewed journals were included. Study quality was assessed using the Newcastle–Ottawa Scale. Results: A total of 75 studies were included. Clinical success rates of 40.9% to 100% were reported. Reported adverse event (AE) rates ranged widely from 5.7% to 85.7%. Comparative studies suggest a higher risk of nephrotoxicity during intermittent infusion compared to continuous infusion. Reported line-related AE ranged from 1.1% to 5.7% and readmission risks associated with vancomycin use were inconsistent across studies. Conclusions: This systematic review shows that vancomycin is an effective agent to use in OPAT setting, however its use is associated with a risk of adverse events. The findings of this study underscore the need for a dedicated multidisciplinary OPAT team to ensure proper follow-up and tailored vancomycin management in the outpatient setting.