Cryptotanshinone (CTS) was reported to repress a variety of systemic inflammation and alleviate cardiac fibrosis, but it is still unclear whether CTS could prevent radiation-induced lung injury (RILI). Here, we investigated the effects and underlying mechanisms of CTS on a RILI rat model. Our data revealed that CTS could efficiently preserve pulmonary function in RILI rats and reduce early pulmonary inflammation infiltration elicited, along with marked decreased levels of IL-6 and IL-10. Moreover, we found that CTS is superior to prednisone in attenuating collagen deposition and pulmonary fibrosis, in parallel with a marked drop of HYP (a collagen indicator) and α-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-β1 and NOX-4 expressions, while enhancing the levels of antifibrotic enzyme MMP-1 in lung tissues. It is noteworthy that CTS treatment, in consistent with trichrome staining analysis, exhibited a clear advantage over PND in enhancing MMP-1 levels. However, CTS exhibited little effect on CTGF activation and on COX-2 suppression. Finally, CTS treatment significantly mitigated the radiation-induced activation of CCL3 and its receptor CCR1. In summary, CTS treatment could attenuate RILI, especially pulmonary fibrosis, in rats. The regulation on production and release of inflammatory or fibrotic factors IL-6, IL-10, TGF-β1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.