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Background: Combat-related lower extremity injuries frequently require prolonged tourniquet application to control life-threatening hemorrhage. Although effective for hemorrhage control, prolonged ischemia followed by reperfusion substantially increases the risk of rhabdomyolysis, acute kidney injury (AKI), limb loss, and mortality. The optimal timing of anti-rhabdomyolysis infusion therapy relative to tourniquet release remains uncertain. Methods: This retrospective single-center cohort study analyzed 120 Ukrainian military casualties with combat-related lower extremity injuries requiring prolonged tourniquet application and subsequent surgical management, including fasciotomy and tourniquet release. Patients were divided into two groups based on infusion strategy: standard therapy initiated after tourniquet release and early anti-rhabdomyolysis infusion therapy initiated before tourniquet removal during the ischemic phase. Primary outcomes included dialysis-requiring AKI, limb amputation, and death. Multivariable logistic regression adjusted for baseline physiological severity, including shock index at admission and baseline acid–base status. Model performance was evaluated using Akaike Information Criterion (AIC) and receiver operating characteristic (ROC) analysis. Propensity score–based inverse probability of treatment weighting (IPTW) was applied as a sensitivity analysis. Results: After adjustment, early infusion therapy was independently associated with a reduced risk of dialysis-requiring AKI (adjusted odds ratio [OR] 0.33; 95% confidence interval [CI] 0.13–0.84; p = 0.020), limb amputation (OR 0.32; 95% CI 0.11–0.95; p = 0.040), and mortality (OR 0.23; 95% CI 0.07–0.77; p = 0.017). Adjusted models demonstrated good discriminative ability, with areas under the ROC curve of 0.813 for AKI, 0.838 for amputation, and 0.823 for mortality. Sensitivity analyses using IPTW yielded consistent results. Conclusions: In combat-related lower extremity injuries requiring prolonged tourniquet application, early initiation of anti-rhabdomyolysis infusion therapy prior to reperfusion is associated with significantly reduced risks of severe AKI, limb loss, and death. These findings suggest that preventive renal-protective strategies initiated before tourniquet release may improve outcomes in high-risk military trauma settings and warrant further prospective investigation.