Objective To investigate the correlation between the activation of peripheral blood neutrophil extracellular traps (NETs), oxidative stress levels, and the risk of developing acute respiratory distress syndrome (ARDS) in patients with multiple trauma, thereby providing a basis for the early prediction and intervention of post-traumatic ARDS. Methods This prospective cohort study enrolled 168 patients with multiple trauma admitted to our hospital between February 2023 and September 2025. Peripheral venous blood was collected within 24 hours of admission and on day 3 after treatment initiation. Plasma levels of NETs markers [neutrophil elastase (NE), citrullinated histone H3 (CitH3), myeloperoxidase (MPO)] and oxidative stress indicators [malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx)] were measured. All patients were followed for 28 days post-admission and were categorized into ARDS and non-ARDS groups based on ARDS occurrence during follow-up. Univariate analysis, multivariate logistic regression analysis, and receiver operating characteristic (ROC) curve analysis were used to assess the correlation and predictive value of NETs and oxidative stress levels for ARDS risk. Results All 168 patients completed the 28-day follow-up. During follow-up, 42 patients (25.0%) developed ARDS. The ARDS group had significantly higher ISS scores, longer mechanical ventilation duration, and a higher proportion of surgical interventions, but lower Glasgow Coma Scale (GCS) scores at admission compared to the non-ARDS group (all P<0.05). At both 24 hours post-admission and on day 3 post-treatment, the ARDS group exhibited significantly higher levels of NE, CitH3, MPO, and MDA, and significantly lower levels of SOD and GPx compared to the non-ARDS group (all P<0.05). By day 3 post-treatment, levels of the aforementioned NETs markers and MDA had decreased, while SOD and GPx levels had increased in both groups; however, the magnitude of improvement was significantly smaller in the ARDS group (all P<0.05). Repeated measures ANOVA revealed statistically significant "time × group" interaction effects for NE, CitH3, MPO, MDA, SOD, and GPx levels (all P<0.05). Multivariate logistic regression analysis identified higher levels of NE, CitH3, MPO, and MDA at 24 hours post-admission as independent risk factors for ARDS, while higher levels of SOD and GPx at the same timepoint were independent protective factors (P<0.05). ROC analysis showed that the combination of plasma NE, CitH3, MPO, MDA, SOD, and GPx levels at 24 hours post-admission predicted ARDS risk with an AUC of 0.811 (95%CI: 0.728-0.895), which was significantly superior to the predictive efficacy of any single indicator alone (Z=3.344, 3.391, 3.069, 2.208, 2.794, 2.021, respectively; all P<0.05). Conclusion Enhanced peripheral blood NETs activation and oxidative stress imbalance are closely associated with an increased risk of ARDS in patients with multiple trauma. NE, CitH3, MPO, MDA, SOD, GPx are independent influencing factors for ARDS risk. Combined dynamic monitoring of these indicators can effectively enhance the predictive power for ARDS risk.