In 2008, a clinical practice guideline (CPG) was developed for the prevention of infections among combat casualties and was later revised in 2011. We evaluated utilization of antimicrobials within 48 hours following injury in the combat zone over a 5-year period (June 2009 through May 2014) with regard to number of regimens, type of antimicrobial, and adherence to the 2011 CPG. The study population consisted of 5,196 wounded military personnel. Open fractures and skin and soft-tissue injuries were the most frequent injuries. Closed injuries had the highest overall compliance (83%), whereas open fractures and maxillofacial injuries had significant improvement in compliance from 2009–2010 (34 and 50%, respectively) to 2013–2014 (73 and 76%, respectively; p < 0.05). Part of the improvement with open fractures was a significant reduction of expanded Gram-negative coverage (61% received it in 2009–2010 compared to 7% in 2013–2014; p < 0.001). Use of Gram-negative coverage with maxillofacial injuries also significantly declined (37–12%; p = 0.001). Being injured during 2011–2014 compared to 2009–2010 was associated with CPG compliance (p < 0.001), while high injury severity scores (≥10) and admission to the intensive care unit in Germany were associated with noncompliance (p < 0.001). Our analysis demonstrates an increasing trend toward CPG compliance with significant reduction of expanded Gram-negative coverage.