Acute radiodermatitis is a type of skin injury caused by tumor radiotherapy. Compound Dahuang Baiji spray (CDBS) is a traditional Chinese medicine spray made from Dahuang and Baiji decoction. In the present study, we aimed to investigate the effects and mechanisms of CDBS on radiation dermatitis. We analyzed the main components of CDBS using High Performance Liquid Chromatography (HPLC). Through network pharmacology prediction, the target of Dahuang and Baiji was identified as arachidonate 5-lipoxygenase (ALOX5), associated with inflammation. Therefore, we constructed radiodermatitis rat models and treated them with CDBS for 14 d. Skin samples were collected from the rats' injured skin tissues, and pathological changes, oxidative stress indicators, inflammatory cytokines, and ALOX5 expression were detected using techniques such as HE staining, blood parameters analysis, ELISA, Real-time qPCR, and Western blot. The characteristic appearances of radiodermatitis were observed in different rat groups which indicated that the skin injury score in the model group was at grade II and was at grade I in the CDBS group. In addition, the HE results showed that CDBS reduced the necrosis of collagen fibers and inflammatory cell infiltration in the dermis of the radiodermatitis rats. Moreover, compared to the model group, CDBS significantly decreased leukocytes, lymphocytes, and neutrophils in the blood, as well as levels of IL-2, LTB4, 5-LO, NO, and ALOX5 expression in rat blood. Our findings suggest the therapeutic effect of CDBS on radiodermatitis by downregulating ALOX5 to inhibit inflammation, potentially serving as a radiodermatitis therapy.