Objective: To determine the optimal timing of antibiotic administration and its impact on surgical site infection (SSI) rates in patients with open fractures. Methods: A retrospective cohort study was conducted involving 426 patients with grade I–III open fractures admitted to a Level 1 trauma center between January 2019 and December 2023. Patients were stratified into two groups based on the time from injury to first antibiotic dose: the early group (≤1 hour, n=218) and the delayed group (>1 hour, n=208). The primary outcome was the incidence of SSI within 30 days postoperatively. Secondary outcomes included the need for revision surgery, length of hospital stay, and 90-day mortality. Results: The early antibiotic group exhibited a significantly lower SSI rate (8.3% vs. 22.1%, P<0.001) compared to the delayed group. Patients in the early group also had a lower rate of revision surgery (5.5% vs. 14.4%, P<0.01), shorter hospital stay (12.4 ± 3.1 days vs. 18.7 ± 4.2 days, P<0.001), and comparable 90-day mortality (2.3% vs. 3.4%, P>0.05). Multivariate regression analysis identified delayed antibiotic administration (>1 hour) as an independent risk factor for SSI (OR=2.89, 95% CI=1.67–5.01, P<0.001). Conclusion: Administration of antibiotics within 1 hour of injury significantly reduces SSI rates and improves clinical outcomes in open fracture trauma patients, supporting current clinical guidelines advocating for prompt antibiotic prophylaxis in this population.