Background <p>Acute respiratory distress syndrome (ARDS) is characterized by acute diffuse lung injury, with pulmonary fibrosis (PF) being a significant complication. The expression patterns and functional role of miR-548a-3p in ARDS and associated PF remain unexplored.</p> Purpose <p>This study aims to delineate the diagnostic and prognostic significance of miR-548a-3p in ARDS and elucidate its underlying molecular mechanisms.</p> Methods <p>Serum miR-548a-3p levels in ARDS patients were quantified using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Diagnostic value was evaluated via receiver operating characteristic (ROC) curves and binary logistic regression, and prognostic significance via Kaplan-Meier analysis and Cox regression. Interleukin-6 (IL-6)/Interleukin-8 (IL-8) levels were measured via enzyme-linked immunosorbent assay (ELISA). Potential targets were screened (NCBI/miRDB) and binding validated by dual-luciferase reporter assays. In lipopolysaccharide (LPS)-injured BEAS-2B cells, miR-548a-3p/Oncostatin M (OSM) regulation effects were examined via ELISA, Cell Counting kit-8 (CCK-8), and flow cytometry.</p> Results <p>ARDS patients exhibited decreased miR-548a-3p expression, which correlated negatively with IL-6 and IL-8. Furthermore, miR-548a-3p effectively discriminated between ARDS patients and healthy individuals and served as a predictor of ARDS. In LPS-injured BEAS-2B cells, miR-548a-3p overexpression promoted proliferation, suppressed apoptosis, and reduced inflammation. OSM was identified as a direct target of miR-548a-3p through database screening and experimental validation. OSM overexpression reversed the protective effects of miR-548a-3p on LPS-injured lung epithelial cells.</p> Conclusions <p>This study is the first to reveal that miR-548a-3p exerts protective effects in ARDS by targeting OSM, underscoring its great potential as a novel diagnostic and prognostic biomarker.</p>