Background: The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury. Methods: We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. Medline, embase, and cochrane databases were searched. Results: The literature search yielded 1,314 unique articles. Fifteen preclinical studies and eight clinical studies fulfilled the in-and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g., ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps, and prostaglandins. High-dose ASA may be the drug of choice. A meta-analysis of three clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36-0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality. Conclusion: This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models are being evaluated to guide optimal timing and dose, before prospective randomized trials.