Objective: To investigate the protective effect of Panax Notoginseng Saponins (PNS) on radiation-induced heart disease (RIHD) in rats and explore its underlying mechanism. Methods: A total of 50 rats were randomly divided into 5 groups using a random number table: normal control group, radiation-only group, and low-, medium-, and high-dose PNS intervention groups, with 10 rats in each group. Except for the normal control group, rats in the other four groups received a single 20 Gy cardiac irradiation. Rats in the low-, medium-, and high-dose PNS groups were intragastrically administered with 10 mg/kg, 30 mg/kg, and 60 mg/kg PNS, respectively, while those in the normal control and radiation-only groups received an equal volume of normal saline. The administration was initiated on the day of irradiation and continued daily for 4 weeks after radiotherapy. After irradiation, serum levels of cardiac troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), malondialdehyde (MDA), superoxide dismutase (SOD), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and transforming growth factor-β1 (TGF-β1) were detected. Pathological changes of myocardial tissues were observed using hematoxylin-eosin (HE) staining. Western blot was performed to determine the protein expression levels of TGF-β1 and Smad3 in myocardial tissues. Results: Compared with the normal control group, the radiation-only group showed increased serum levels of cTnI, CK-MB, MDA, ICAM-1, TNF-α, IL-1β, and TGF-β1 (P<0.05), decreased serum SOD level (P<0.05), and elevated myocardial pathological score (P<0.05). Compared with the radiation-only group, all PNS intervention groups exhibited reduced serum levels of cTnI, CK-MB, MDA, ICAM-1, TNF-α, IL-1β, and TGF-β1 (P<0.05), increased serum SOD level (P<0.05), and decreased myocardial pathological score (P<0.05). The changes of these indexes were dose-dependent in the low, medium and high dose groups (P<0.05). Conclusion: PNS exerts a protective effect against RIHD in rats, and its mechanism may be associated with regulating oxidative stress, alleviating inflammatory response, and inhibiting the TGF-β1/Smad3 signaling pathway.