The main pathological change of radiation-induced heart disease is fibrosis. Emerging evidence has indicated that Astragalus membranaceus and its extractant, Astragalus saponin (AST), were used for treating fibrosis diseases. In the present study, the effects of AST on fibrosis damage induced by irradiation were determined. After being irradiated with 1 or 2-Gy X-rays, obvious changes of endoplasmic reticulum morphology were observed in cardiac fibroblasts (CFs), suggesting that its protein processing function was imbalanced, which indirectly indicated that fibrosis damage was caused by irradiating CFs. The expression levels of TGF-β1 and collagen I (Col-1) were increased at 48-h post-irradiation. Administration of 20 μg/ml AST reduced the production of reactive oxygen species in irradiated CFs and decreased the expression of Col-1, TGF-β1, and p-Smad2/3. Polymerase chain reaction (PCR)-array analysis showed that there were ∼30 genes which were mainly classified into extracellular matrix, remodeling enzymes, inflammatory cytokines/chemokines, and TGF-β superfamily, were up-regulated after treatment with 1-Gy X-ray, whereas most of these genes were down-regulated when pretreated with 20 μg/ml of AST. In addition, TIMP1 and Smad7 genes that were down-regulated after treatment with 1-Gy X-ray were up-regulated when pretreated with 20 μg/ml of AST. In conclusion, radiation-induced fibrosis damage was observed at a cellular level. AST attenuated this fibrosis damage effect in irradiated CFs and this anti-fibrosis effect may be closely related to its antioxidant action. The involvement of fibrosis-related molecules in irradiated CFs was systematically demonstrated by a PCR array for the first time. AST reversed the expression of the majority of genes changed by irradiation, which further confirmed its anti-fibrosis effect.