Background <p>Mechanical ventilation (MV) is an essential life support for patients with acute respiratory distress syndrome (ARDS). However, mechanical ventilation in patients with ARDS can cause ventilator-induced lung injury (VILI). Simvastatin can alleviate acute lung injury by anti-inflammatory and enhancing endothelial barrier. The present study aimed to evaluate whether simvastatin could attenuate VILI in mice with ARDS.</p> Methods <p>Mice were randomized into six groups: the sham (S), LPS (L), MV (V), LPS/MV (LV), LPS/MV/simvastatin (MS) and LPS/MV/GSK484 (MG) groups. The mice in the L group received LPS but not ventilation, the mice in the V group received only MV, and the mice in the LV, MS and MG groups received LPS and MV. Additionally, MS group were treated with simvastatin, MG group were treated with GSK484, and the other mice were injected with saline, starting three days prior to mechanical ventilation. The PaO₂/FiO₂ ratio and wet‒dry weight ratio were calculated. Histopathological changes were observed, and injury scores were calculated. Inflammatory factor levels in the bronchoalveolar lavage fluid (BALF) were detected. Peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE) and citrullinated histone 3 (Cit-H3) in the lung tissue were detected, apoptosis were also evaluated.</p> Results <p>All indices were improved in group S compared with the other groups. The lung injury score and wet‒dry weight ratio were lower, the PaO₂/FiO₂ ratio was greater, inflammatory factor levels in the BALF were lower, PAD4, NE, and Cit-H3 expression was lower, and apoptosis was decreased in the MS and MG groups compared with the LV group.</p> Conclusions <p>Simvastatin attenuated VILI in mice with ARDS, potentially via reductions in neutrophil extracellular traps (NETs) generation and apoptosis.</p>