Objective:To investigate the association between postoperative neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) and the development of surgical site infection (SSI) in patients with open extremity fractures, and to evaluate their utility for early risk stratification and optimization of antimicrobial stewardship. Methods: We conducted a retrospective cohort study involving 115 adult patients with open extremity fractures admitted to Yuhang District First People’s Hospital between January 2023 and December 2025. Patients were categorized into an infection group (n = 22, 19.1%) and a non-infection group (n = 93) based on the occurrence of SSI within 30 days postoperatively, per Centers for Disease Control and Prevention (CDC) and AO Foundation criteria. Baseline demographics, Gustilo-Anderson classification, injury-to-surgery interval, preoperative and serial postoperative (days 1, 3, and 7) complete blood count parameters (used to compute NLR and MLR), operative details, and clinical outcomes were extracted from electronic medical records. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of SSI. Receiver operating characteristic (ROC) curve analysis was used to assess discriminatory performance, including area under the curve (AUC), optimal cut-off values (determined by Youden index), sensitivity, and specificity. Results: The infection group exhibited a significantly higher proportion of Gustilo-Anderson type III injuries (50.0% vs. 20.4%, P < 0.01) and longer injury-to-surgery intervals (>6 hours: 45.5% vs. 24.7%, P = 0.042). Median NLR [8.12 (5.85–11.45)] and MLR [1.08 (0.82–1.45)] measured during postoperative days 1–3 were markedly elevated relative to the non-infection group [4.25 (3.10–5.76) and 0.67 (0.51–0.89), respectively; both P < 0.001]. Multivariate logistic regression confirmed that postoperative NLR (adjusted odds ratio [aOR] = 1.26, 95% CI: 1.12–1.41, P < 0.001) and MLR (aOR = 2.08, 95% CI: 1.42–3.05, P < 0.001) were independent predictors of SSI. ROC analysis demonstrated that NLR achieved an AUC of 0.805 (cut-off: 6.72; sensitivity: 76.5%; specificity: 77.4%), MLR an AUC of 0.778 (cut-off: 0.90), and their combination yielded superior discrimination (AUC = 0.859; sensitivity: 82.1%; specificity: 80.6%). Patients in the infection group experienced significantly prolonged hospitalization [16.5 (11–22) vs. 8.5 (6–11) days, P < 0.001] and higher reoperation rates (31.8% vs. 5.4%, P < 0.01). Conclusion: Early postoperative elevation of NLR and MLR constitutes a simple, cost-effective, and clinically actionable inflammatory signature predictive of SSI following open extremity fractures. Serial monitoring of these ratios may facilitate timely risk stratification, guide intensified antimicrobial and wound management strategies, and support personalized postoperative surveillance.