Acute lung injury (ALI) describes a form of parenchymal lung disease representing a wide range of severity from short-lived dyspnea to terminal failure of the respiratory system or acute respiratory distress syndrome (ARDS). No sufficient data is addressing the role of oxidative stress and the effect of mast cell stabilizer on lipopolysaccharides (LPS) induced ALI model. This study aimed to investigate the effect of ketotifen on LPS-induced ALI in rats with an explanation of possible underlying mechanisms. Rats were allocated into 4 groups: (1): control group, (2): ketotifen group (received ketotifen 1 mg/kg/day orally for 2 weeks), (3): LPS group received LPS 5mg/kg intratracheal single dose at 5th day ,and (4): ketotifen+LPS group: received both ketotifen plus LPS in the same previous doses. Rats were sacrificed after 2 weeks. The lung oxidative damage effect of LPS was evaluated by measuring the lung tissue level of malonaldehyde (MDA) and histopathological assessment. ALI induced by LPS revealed statistically significant improvement in rats treated with ketotifen compared with LPS alone group. These results suggest that ketotifen can protect against LPS-induced ALI. Ketotifen effects rely, at least partially, on its antioxidant effect.