Objective <p>To investigate the effect and mechanism of panaxadiol saponin component (PDS-C) in radiation-induced cardiac injury (RIHD).</p> Methods <p>BALB/c mice were radiated by X-ray to establish RIHD mouse models, and randomly divided into 3 groups by using a random number table method (<i>n</i>=10 in each group): the mice in the normal control and RIHD model groups received normal saline, and the PDS-C group was treated with PDS-C (80 mg/kg) for 12 weeks. Cardiac function was observed by ultrasound imaging; serum myocardial enzymes were tested; and pathological examination of cardiac tissue was performed. Differentially transcribed genes of cardiac tissue were analyzed between normal and RIHD mice. The expression levels of inflammatory factors and fibrotic proteins were detected by immunohistochemistry, immunohistofluorescence and Western blot, respectively. Irradiation H9c2 cells were incubated by PDS-C (20, 40, 80 mg/L) for detecting inflammatory factors and fibrotic proteins. Irradiation H9c2 cells were incubated by both phorbol 12-myristate 13-acetate (PMA) as nuclear factor κB (NF-κB) activator and BAY11-7082 as inhibitor to verify the effects of PDS-C on NF-κB transcription factor.</p> Results <p>Differentially expressed genes between normal and RIHD mice were involved mainly in the NF-κB transcription factor, which is related to cardiac inflammation. PDS-C effectively increased the cardiac ejection fraction and fractional shortening (<i>P</i>&lt;0.05), but decreased the levels of the myocardial enzymes aspartate aminotransferase, creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase in RIHD mice (<i>P</i>&lt;0.05). Pathological examination of cardiac tissue revealed obvious edema, severe necrosis, and nuclear pyknosis in RIHD mice; however, PDS-C clearly alleviated the extent of cardiac damage. Furthermore, PDS-C downregulated interleukin (IL)-1, IL-6, Smad2, connective tissue growth factor, collagen II and NF-κB (<i>P</i>&lt;0.05). Cytological experiments revealed that PDS-C decreased reactive oxygen species levels in irradiated H9C2 cells (<i>P</i>&lt;0.05), and the expressions of the above inflammatory factors and fibrosis-related proteins were consistent with the results in mouse models.</p> Conclusion <p>PDS-C showed cardioprotective effect in alleviating inflammation and fibrosis through inhibition of the NF-κB signaling pathway.</p>