Objective To investigate the value of serum angiopoietin like protein 4 (ANGPTL-4), growth differentiation factor 15 (GDF-15) and fibroblast growth factor 21 (FGF-21) in evaluating the condition and predicting the prognosis of patients with acute respiratory distress syndrome (ARDS). Methods The clinical data of 147 patients with ARDS admitted in our hospital from January 2019 to December 2021 were collected. The levels of serum ANGPTL-4, GDF-15 and FGF-21 in the ARDS patients on the day of admission were detected. According to the oxygenation index(OI), the ARDS patients were divided into a mild group with 38 cases (200 mm Hg <OI≤300 mm Hg), a moderate group with 63 cases (100 mm Hg <OI≤200 mm Hg) and a severe group with 46 cases (OI≤100 mm Hg). According to the survival within 28 days after entering the intensive care unit, the ARDS patients were divided into a survival group with 90 cases and a death group with 57 cases. Multivariate logistic regression analysis was used to analyze the risk factors of death in the patients with ARDS. Receiver operator characteristic curve were drawn to analyze the value of serum ANGPTL-4, GDF-15 and FGF-21 levels in predicting the prognosis of ARDS patients. Pearson correlation was used to analyze the correlation between serum ANGPTL-4, GDF-15 and FGF-21 levels. Results The levels of serum ANGPTL-4, GDF-15 and FGF-21 in the death group were significantly higher than those in the survival group (all P<0.001). The levels of serum ANGPTL-4, GDF-15 and FGF-21 in the severe group were significantly higher than those in the mild group and the moderate group (all P<0.001). Multivariate logistic regression analysis showed that the levels of OI (OR=2.416, 95%CI 1.615 - 5.470), APACHEⅡ score (OR=2.795, 95%CI 1.973 - 6.874), SOFA score (OR=1.692, 95%CI 1.170 - 3.105), ANGPTL-4 (OR=1.951, 95%CI 1.360 - 4.208), GDF-15 (OR=2.583, 95%CI 1.804 - 6.195) and FGF-21 (OR=3.116, 95%CI 2.513 - 9.307) were the risk factors of death in patients with ARDS (P<0.05). The area under the ROC curve of combination of ANGPTL-4, GDF-15 and FGF-21 was the highest (0.953, 95%CI 0.892 - 0.998) for prediction the death of ARDS patients, with a sensitivity of 98.0% and specificity of 87.3%. Correlation analysis showed that serum ANGPTL-4 level was positively correlated with GDF-15 and FGF-21 in the ARDS patients (P<0.001). Conclusions The elevated levels of serum ANGPTL-4, GDF-15 and FGF-21 are related to the severity and death of ARDS patients. The combined detection of serum ANGPTL-4, GDF-15 and FGF-21 is helpful to predict the prognosis of ARDS patients.