Background: Owing to its antioxidant, anti-inflammatory and anti-fibrotic properties, alpha-lipoic acid (ALA) has been evaluated in a diversity of degenerative diseases and experimental toxicological studies. Aim of the Work: This study was performed to assess the ability of ALA to reverse the histological and biochemical alterations that take place in the rat lungs after exposure to methotrexate. Materials and Methods: This study was done using thirty-two male Wistar albino rats (180–220 g). The animals were divided into four equal groups. The control group: received distilled water by oral gavage for ten days and injected intraperitoneally (i.p.) with1 ml of physiologic saline (0.09% NaCl) solution on the fourth day. ALA group: received ALA (200 mg/kg once daily) dissolved in distilled water and given by oral gavage for ten days. Methotrexate (MTX) group: injected with a single dose of 20mg/kg MTX i.p. on the fourth day of the study. MTX+ALA group: received an oral dose of ALA (200 mg/kg) for ten days and a single dose of MTX (20mg /kg) i.p. on the fourth day. By the end of the experiment, all the animals were anaesthetized using phenobarbital 3%. Blood samples were collected to measure c-reactive protein (CRP). The lungs were dissected out and prepared for tissue homogenates, routine histological study and caspase-3 immunohistochemical evaluation. Results: In the MTX group, there were high levels of CPR, glutathione (GSH) and malondialdehyde (MDA) with reduction of superoxide dismutase (SOD) and catalase (CAT) activities. Lung sections revealed marked inflammatory cells infiltration, thickening of interalveolar septa, congested blood vessels, intrapulmonary hemorrhages, abundant collagen fibers and significant expression of caspase-3. In ALA+MTX group, there was an overt improvement in lung histoarchitecture. Additionally, SOD activity. CRP, MDA levels and caspase-3 expression were significantly less. Conclusion: Administration of ALA can work against oxidative damage in the lung induced by MTX.