Background: Radiation‐induced acute lung damages are refractory side effects in lung cancer radiotherapy (RT). Prospective study investigates the possible role of piperine (Pip) as anti-inflammatory agent against γ-rays-induced lung tissue lesions in an applicable rat model. Materials and Methods: Fifty-six Sprague-Dawley rats were divided into four groups: Control, rats were administered the vehicle by gastric tube for 6-weeks, Pip-treated, (each rat received 40mg Pip/kg body-weight; once daily, orally for 6weeks), irradiated, (animals subjected to a single dose of whole body γ-rays (12Gy), and Pip-treated & irradiated, (each rat received the Pip-dosages, then one hour later after the last treatment, rats were exposed to 12Gy γ-rays.  Results: The administration of Pip to rats pre-irradiation was significantly abolish the radiation-induced alleviation in lungs catalase (CAT) and glutathione peroxidase (PGx) activities and reduced glutathione (GSH) content and significantly limited the elevation in serum tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels compared to irradiated group. The histopathological findings in lung tissues of irradiated group, showed partial desquamation of bronchiolar epithelial with peri-bronchiolar round cell infiltration and serous exudates, in some cases lung presented sero-fibrinous pneumonia with emphysema and collapse of some alveoli with thickness of inter-alveolar septa, while in Pip-treated & irradiated group, lung tissues showed minimum injury with or without few degenerative changes. Conclusion: Pip acts as a potent scavenger of free radicals to prevent and/or ameliorates the harmful effects of γ-rays. To our knowledge, this is the preliminary report of Pip mediated γ-rays induced lung inflammation in-vitro.