Ionizing radiation-induced pulmonary injury is a major limitation of radiotherapy for thoracic tumors. We have demonstrated that triptolide (TPL) could alleviate IR-induced pneumonia and pulmonary fibrosis. In this study, we explored the underlying mechanism by which TPL mitigates the effects of radiotoxicity. The results showed that:(1) Alveolar macrophages (AMs) were the primary inflammatory cells infiltrating irradiated lung tissues and were maintained at a high level for at least 17 days, which TPL could reduce by inhibiting of the production of macrophage inflammatory protein-2 (MIP-2) and its receptor CXCR2.(2) Stimulated by the co-cultured irradiated lung epithelium, AMs produced a panel of inflammative molecules (IMs), such as cytokines (TNF-a, IL-6, IL-1a, IL-1ß) and chemokines (MIP-2, MCP-1, LIX). TPL-treated AMs could reduce the production of these IMs. Meanwhile, AMs isolated from irradiated lung tissue secreted significantly high levels of IMs, which could be dramatically reduced by TPL.(3) TPL suppressed the phagocytosis of AMs as well as ROS production.Our results indicate that TPL mitigates radiation-induced pulmonary inflammation through the inhibition of the infiltration, IM secretion, and phagocytosis of AMs.