Radiation is capable of inducing reactive oxygen species (ROS), cytokines, chemokines, and growth factors as well as inflammatory cells. Radiation has been termed pro-inflammatory in nature. The current study aims to assess the protective effects of ivermectin against high doses of γ-irradiation by inspecting the effect on inflammatory mediators such as lung receptors toll-like receptors (TLR4), transforming growth factor beta (TGF-β), fibroblast growth factor (FGF), and nuclear factor-kappa B (NF-κβ) in adult male albino rats. Ivermectin was administered orally for 14 days at a dose of 3.7 mg/kg/day and then male albino rats were subjected to a high dose of γ-radiation (30 Gy), which was divided into 10 fractions / five times per week. In addition to increasing the activity of lactate dehydrogenase A (LDHA) in lung tissue, gamma radiation also significantly disrupted the antioxidant system, resulting in lung damage through increased levels of prostaglandin 2 (PGE2), TLR4, TGF-β, NF-κβ, and FGF. In the present work, ivermectin minimized pulmonary damage, through suppression of ROS formation and the restoration of virtually normal levels of FGF, PGE2, TGF-β, NF-κβ, and TLR4 in the lungs, as well as the activities of MAPK and LDHA. The biochemical outcomes were validated by the histological analysis. In conclusion, Ivermectin protects against γ-radiation-induced lung damage by lowering fibroblast differentiation, production of reactive oxygen species and cytokines. Ivermectin mitigates lung damage by modulating TLR4/NF-κβ /MAPK pathways.