Acute respiratory distress syndrome (ARDS) is a serious lung disease that significantly increases morbidity and mortality in combat casualties as well as civilian patients. However, accurate diagnosis of ARDS is challenging, especially in military prolonged field care or austere environments with limited access to advanced diagnostic tools and absence of specialized medical providers. Several prognostic biomarkers have previously been proposed. However, due to the heterogeneous etiology of ARDS, a rapid and reliable biomarker for precisely predicting ARDS is still not available. The objective of this study was to analyze high mobility group box 1 (HMGB1), syndecan-1 (SDC-1), and C3a biomarkers to determine their ability to predict the onset of ARDS in an animal model of smoke inhalation (SI) and burn injury. Serum samples taken from several cohorts of anesthetized swine that underwent SI and 40% TBSA burn injuries were tested for the presence of HMGB1, SDC-1, and C3a. All animals were monitored in an animal Intensive Care Unit (ICU) for up to 72 hours post-injury (PI). Blood samples were drawn at baseline (BL), post injury (PI), 1, 3, 6, 12, 24, 48, and 72 hours PI then subsequently used for analysis of HMBG1, SDC-1, and C3a using ELISA assays. A receiver operating characteristic (ROC) analysis was used to determine the diagnostic ability of the biomarkers and incidence of ARDS and survivability. 69% of swine developed ARDS as determined by their P/F ratio at a median of 22 hours (IQR, 9-43) PI. 74% of swine survived to end of-study. SDC-1 and C3a were not correlated with ARDS development or mortality. HMGB1 levels in serum were significantly higher in swine with ARDS compared to those that did not develop ARDS (p<0.05). ROC analysis revealed that HMGB1 levels correlate with ARDS development at 6 hours PI (AUROC=0.77, cut-off=24.10 ng/mL, sensitivity=73.08%, and specificity=83.33%). HMGB1 levels also correlate with survival at 6 hours PI (AUROC=0.82, cut-off=31.39 ng/mL, sensitivity=75.00%, and specificity=80.00%). Our data suggest HMGB1 is a sensitive biomarker of ARDS disease progression. Therefore, HMGB1 may serve as a rapid diagnostic biomarker for predicting trauma-induced ARDS and survivability in military casualties with both SI and burn injuries.