Radiation‑induced lung injury (RILI) is a major complication of thoracic radiotherapy that starts as exudative inflammation and proceeds to lung fibrosis, and additional studies are required to develop methods to ameliorate RILI. The aim of this study was to explore whether the nicotinic acetylcholine receptor subtype‑7 (α7‑nAChR) agonist GTS‑21 has a protective effect against RILI. C57BL6 mice were irradiated with 12 Gy to induce a mouse model of RILI. Some of the mice received an i.p. injection of 4 mg/kg GTS‑21 for three days with or without radiation treatment. Mice were sacrificed at 1, 3, 7, 14 and 21 days and at 3 and 6 months after irradiation. The results showed that GTS‑21 treatment significantly relieved RILI by decreasing TNF‑α, IL‑1β and IL‑6 production in serum via inhibition of NF‑κB activation and downregulation of TLR‑4 and HMGB1 expression in the lungs. In addition, we found that GTS‑21 may regulate the MMP/TIMP balance in RILI. Finally, we found that GTS‑21 inhibited NOX‑1 and NOX‑2 expression, which subsequently reduced ROS levels and Hif‑1α expression in RILI. However, GTS‑21 showed little effect on lung tissue without radiation exposure. The results above were also validated in RAW264.7 macrophages. Our results showed that activation of the cholinergic anti‑inflammatory pathway via the α7‑nAChR agonist GTS‑21 reduced RILI. The protective effect of GTS‑21 against RILI is partly attributed to inhibition of the HMGB1/TLR4/NF‑κB pathway and ROS production. Thus, activation of the α7‑nAChR pathway may lead to new possibilities in the therapeutic management of RILI.