Open fractures are associated with a high risk of surgical site infection (SSI) due to impaired vascularity, extensive soft tissue injury, and contamination. Despite prompt systemic antibiotic administration being the standard of care, infection rates remain substantial. The adjunctive use of topical antibiotics has been proposed to further reduce this risk. A systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, and the Cochrane Library databases were searched for studies published between 2015 and 2025. Six studies (one randomized controlled trial and five cohort studies) involving 2,982 patients were included, of whom 758 received adjunctive topical antibiotics. The pooled analysis demonstrated a significantly lower SSI rate in patients receiving both systemic and topical antibiotics compared with systemic antibiotics alone (7.26% vs. 10.12%; p=0.0197). No significant difference was observed between monotherapy with vancomycin and dual therapy with vancomycin plus tobramycin (p=0.0602). No increase in systemic adverse events was reported, although one study noted a higher incidence of wound-healing complications with vancomycin powder. Adjunctive topical antibiotic administration was associated with a statistically significant reduction in SSI rates following open fractures. However, heterogeneity in study design, outcome definitions, and interventions limits the strength and generalizability of the evidence. Large, high-quality randomized trials are needed to establish optimal regimens, evaluate long-term safety, and determine cost-effectiveness.