Radiation-induced lung injury (RILI) is a common complication of cancer radiotherapy, yet effective treatments remain elusive. Compound Kushen injection (CKI), a traditional Chinese medicine (TCM) formula, is widely used in clinical practice for treating radiation-related diseases and as an adjunct therapy for cancer and has demonstrated some effectiveness. However, the mechanisms underlying CKI intervention in RILI and its role in cancer adjunctive therapy remain unclear. In this study, we refined previous statistical approaches and successfully integrated quantitative data on the compounds in CKI. We constructed a network-based holistic target model and developed modular biological networks to explore the modular regulatory effects of CKI in RILI. Through this network-based analysis, we identified specific alkaloid components of CKI that contribute to its therapeutic effect in alleviating RILI. Furthermore, through transcriptomic analysis, we confirmed that oxidative stress plays a central role in the treatment of RILI by CKI. The modular regulatory effects of CKI have been validated in animal models of irradiation, demonstrating the ability of CKI to alleviate oxidative stress, reduce inflammation, regulate immune responses, and inhibit apoptosis. In addition, we demonstrated that nuclear factor erythroid 2-related factor 2 (NRF2) serves as a key mediator of the antioxidant effects of CKI. Matrine and sophoridine, representative alkaloids in CKI, exhibit binding interactions with NRF2. CKI promotes the nuclear translocation of NRF2, and NRF2 activates its downstream targets, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), to suppress oxidative stress in RILI. This, in turn, inhibits the expression of inflammatory molecules, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS), while promoting the activity of antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase-4 (GPX-4), thereby exerting therapeutic effects on RILI.