Sepsis-related acute respiratory distress syndrome (ARDS) has worse clinical outcomes than non-sepsis-related ARDS. Presepsin is known to be elevated in sepsis, but little is known about its discriminatory ability and prognostic evaluation in patients with sepsis-related ARDS. This study was a multicenter prospective cohort study of 225 consecutive ARDS patients. Patients with sepsis-related ARDS had higher presepsin levels than patients with non-sepsis-related ARDS (P < 0.001). The area under the receiver operating characteristic (ROC) curve of presepsin (0.81) was significantly greater than that of PCT (0.62) in diagnosing sepsis-related ARDS (P = 0.001). Among patients with sepsis-related ARDS, presepsin levels were significantly higher in non-survivors than in survivors (P < 0.001). Presepsin was found to be an independent predictor of in-hospital mortality in sepsis-related ARDS. Based on ROC analysis, the addition of presepsin improved discrimination based on SOFA or APACHE II scores from 0.77 to 0.87 or 0.73 to 0.85 (all P < 0.05), respectively. The levels of plasma presepsin were positively correlated with disease severity, as determined by the SOFA score in the sepsis-related ARDS group (P < 0.001). Presepsin is a valuable biomarker for early stratification of sepsis-related ARDS. Higher plasma presepsin levels are associated with increased mortality in sepsis-related ARDS.