Erdosteine is a mucolytic agent with antioxidant and anti-inflammatory effects. We evaluated the protective effect of erdosteine pretreatment on oleic acid (OA)-induced acute lung injury. Twenty-four male Wistar Albino rats were assigned to four treatments: control (oral saline + 50 μL intravenous [i.v.] saline), OA (oral saline + 50 μL i.v. OA), erdosteine (150 mg/kg oral erdosteine + 50 μL i.v. saline), and OA + erdosteine (150 mg/kg oral erdosteine + 50 μL i.v. OA). Four hours after OA injection, lung tissues were excised for biochemical and histopathologic evaluation. OA treatment increased lung weight and tissue malondialdehyde and protein carbonyl levels, but erdosteine pretreatment significantly suppressed these changes (0.57 ± 0.1 g, 3.27 ± 0.48 nmol/mg protein, and 33.57 ± 4.6 nmol/mg protein, respectively, for OA versus 0.36 ± 0.02 g, 1.84 ± 0.15 nmol/mg protein, and 22.10 ± 2.55 nmol/mg protein, respectively, for OA + erdosteine; P < 0.05 for all). Erdosteine pretreatment increased the activities of the antioxidant enzymes, catalase, and glutathione peroxidase (0.16 ± 0.03 k/g and 0.3 ± 0.01 U/mg protein, respectively, for OA versus 0.33 ± 0.05 k/g and 0.34 ± 0.01 U/mg protein, respectively, for OA + erdosteine; P < 0.05 for both). Erdosteine pretreatment also significantly decreased the median numbers of intra-alveolar macrophages and intra-alveolar and interstitial neutrophils (29.0, 17.0, and 15.0, respectively, for OA versus 12.5, 4.0, and 6.5, respectively, for OA + erdosteine; P < 0.001 for all). Erdosteine pretreatment increased the activities of antioxidant enzymes and decreased macrophage and neutrophil accumulation, thereby ameliorating the inflammatory effects of OA treatment. Erdosteine pretreatment prevents OA-induced oxidative stress and inflammation and protects the lung tissue against acute lung injury.