In patients with severe lung injury, extracorporeal life support (ECLS) enables lung rest, but the optimal strategy is unknown. This study compared liquid lung rest (LLR) versus standard gas rest ventilation in a porcine model of acute lung injury supported by ECLS. Twenty neonatal pigs received oleic acid-induced lung injury and were placed on ECLS. Pigs were ventilated with standard rest settings (peak inspiratory pressure 20 cm H₂O; end expiratory pressure 10 cm H₂O; rate 10 breaths/minute) and randomized to gas ventilation alone or 5 ml/kg perfluorooctylbromide instilled endotracheally (LLR). The study lasted 4 hours with hourly pulmonary compliance measurements. After euthanasia, lung tissue was analyzed histologically, and inflammation was quantified via blood and lung tissue cytokines. All pigs achieved significant lung injury; static compliance decreased by 54%. After 4 hours, compliance was higher with LLR compared with gas ventilation (0.88 ± 0.05 ml/kg/cm H₂O vs. 0.57 ± 0.05, p < 0.001). The LLR resulted in 2.1-fold greater airspace in dependent regions (p < 0.001) and a reduced airspace heterogeneity index (LLR: 0.071 ± 0.004, gas: 0.095 ± 0.010, p = 0.04), suggesting more uniform alveolar recruitment. Tissue interleukin-10 levels were reduced 3.7-fold with LLR (p = 0.02). The LLR improved compliance, alveolar recruitment, and interleukin-10 levels compared with standard gas ventilation, suggesting potential benefit in acute lung injury requiring ECLS.