Mechanical ventilation can cause structural and functional disturbances in the lung termed ventilator-induced lung injury (VILI). The aim of this study was to evaluate whether BML-111, a lipoxin receptor agonist, could attenuate VILI. Following induction of anesthesia and tracheostomy, Sprague-Dawley rats were ventilated with low tidal volume (6 mL/kg) or high tidal volume (20 mL/kg, HVT) for 4 h. Some rats subjected to HVT ventilation received BML-111 or vehicle (saline) by intraperitoneal injection. Some rats subjected to HVT and BML-111(1 mg/kg) received BOC-2 (a FPR2/ALX antagonist) intraperitoneally 30 min before BML-111. Sham rats were tracheotomized without ventilation. Treatment with BML-111 attenuated VILI, as evidenced by improved oxygenation and reduced histological injury compared with HVT-induced lung injury. BML-111 decreased indices of inflammation such as interleukin 1β, interleukin 6, tumor necrosis factor α, and bronchoalveolar lavage neutrophil infiltration. Administration with BML-111 suppressed the decrement of the nuclear factor κB (NF-κB) inhibitor IκB-α, diminished NF-κB activation, and reduced activation of mitogen-activated protein kinase in VILI. This study indicates that BML-111 attenuated VILI via a NF-κB and mitogen-activated protein kinase dependent mechanism. BML-111 may be a promising strategy for alleviation of VILI in patients subjected to mechanical ventilation.