Background: The intention of the present study was to assess the structural affection of the lung following methotrexate (MTX) overdose. The proposed underlying mechanisms involved in lung affection were studied. The possible modulation role of febuxostat over such affection was studied. Materials and methods: Twenty-four rats were divided into three groups: control, MTX-treated, febuxostat-treated. The study was continued for 2 weeks. Lung was processed for histological and immunohistochemical (inducible nitric oxide synthase [iNOS] and cyclooxygenase [COX]-2) studies. Inflammatory markers (tumour necrosis factor alpha [TNF-a], interleukin 1 [IL-1]), Western blot evaluation of nuclear factor kappa B (NF-kB) and oxidative/antioxidative markers were done. Results: Methotrexate-treated group exhibited inflammatory cellular infiltrations, thickened interalveolar septa, dilated congested blood vessels, extravasated blood, and apoptosis. The collagen fibres content increased 3-fold. MTX induced lung affection through oxidative stress (increase MDA/decrease GSH, SOD) and apoptosis. It induced sterile inflammation through an increase of NF-kB (2-fold), IL-1 (3-fold) and TNF-a (3-fold), COX-2 cells (2.5-fold) and iNOS (6-fold). With the use of febuxostat, the normal lung architecture was observed with a bit thickened interalveolar septum and extravasated blood. The collagen fibres content was minimal. Decrement of oxidative stress and sterile inflammation (COX-2 cells and iNOS were comparable to the control group. NF-kB, IL-1 and TNF-a became higher by 34%, 64% and 100%). Conclusions: The overdose of MTX displays inflammatory lung affection with residual fibrosis. It induces lung affection through oxidative stress, apoptosis and sterile inflammation. With the use of febuxostat, the normal lung architecture was preserved with a little structural affection or fibrotic residue. Febuxostat exerts its lung protection through its anti-inflammatory and antioxidant features.