Amethopterin (methotrexate, MTX) is an antimetabolite and antifolate drug with antiflammatory properities and is used to treat autoimmune diseases, such as psoriasis, rheumatoid arthritis and certain types of cancer, such as breast, lymphoma and lung. The present study aimed to study the changes in P53, Bcl-2 and CD68 expression in response to amethopterin-induced lung injury and ameliorating the role of l-carnitine. A total of 36 male albino rats were equally divided into six groups: the first and second groups were the control and l-carnitine groups respectively while the 3rd group was amethopterin rat group; the 4th and 5th groups were co- and post-treated amethopterin rat with l-carnitine respectively and the 6th group was self treated amethopterin rat group. Our results shows that lung in amethopterin-treated rats showed many of histopathological alterations as severe to strong alveolar damage in the form of collapsed alveoli and strong thickened interalveolar septa with heavy infiltration of inflammatory cells. This damage was increased or remaining in self-amethopterin-treated group. Treatment (co- and post) with l-carnitine were improved in the lung structure that was treated with amethopterin. A significant increase in p53 and CD68 and decrease in Bc1-2 immunoreactivity in the lung in amethopterin group is observed when compared with the control group. However, treatment of rats with l-carnitine decreased the intensity of P53-ir and CD68-ir and increased the intensity of Bcl-2 in lung when compared with amethopterin rat group. Co-treatment with l-carnitine improved lung damage induced with amethopterin.