Objective: Pulmonary fibrosis (PF) is an irreversible and untreatable human disease encompasses a large group of chronic lung disorders associated with excessive remodeling, scarring, and fibrosis.The current work was designed to study the harmful effects of methotrexate (MTX) administration on the lung and the possible protective role of Carthmus tinctorius leaves extract. The animals were utilized in this study. Methods:A total of 40 male healthy adult Wistar albino rats with anaverage body weight of 200±25 g, were divided into four groups (10 animals each). G1: control group, G2: MTX group, G3: Carthamus tinctorius (CT), group G4:MTX+Carthamus tinctorius(CT). CT was administered orally at a dose of (40 mg/kg/day) for 4 w to G3 and G4. The (CT) group were performed to explore any toxic effect of the (CT) extract on the lung. Rats of G2 and G4 administered 4 mg/kg dose of MTX orally for 28 d. Rats of G1 were intraperitoneally (i. p) administered with normal saline 0.5 ml ∕ day for four weeks (4wk) to serveas control. The animals were weighed at the beginning, though, and at the end of experiments. Results:The study showed that the relative lung weight was significantly increased at (P˂0.0 1) in MTX-treated animals in comparison to the control group. A combination of CT extract with MTX revealed significant decrease (P<0.01) in the lung relative weight in comparison to MTX group. Histopathological examination revealed that lung injury was less severe in group 3 and 4compared to group 2. The results indicated that CT significantly decreased collagen deposition, hydroxyproline content, and ameliorated pathological changes. Conclusion:The study has clearly identified the importance protective role of CT extract on pulmonary fibrosis induced by methoxerate. We recommended CT as one of therapeutic strategy to amelioratethe lung fibrosis associated with methotrexate therapy.