Panax notoginseng saponin (PNS) constitutes the major effective components of Panax notoginseng, which is widely used to treat microcirculatory disturbance associated diseases. In this study, we designed to investigate the effect of PNS on the treatment of pulmonary fibrosis (PF) and further explored its mechanism. A total of 40 healthy Japanese White rabbits were randomly divided into five groups (control group; PF model group; PNS prevention group; PNS treatment group; and western medicine [prednisone acetate] treatment group). Expression of hydroxyproline (HYP), fibronectin (FN), aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), interleukin-6 (IL-6), and interleukin-8 (IL-8) in serum was detected using corresponding detection kits. Western blot was applied to detect the expression of p50 and p65 in pulmonary tissues. The pathological variations of the cardiac and pulmonary ultrastructure were observed under both the optical and electron microscope. PF models were established successfully. The results showed that compared with the other groups, PNS groups (PNS prevention and treatment group) apparently relieved the cardiopulmonary injury, and reduced IL-6 and IL-8 expression levels in the serum. Furthermore, the PNS groups performed better in relieving cardiopulmonary injurythan other groups. Both the PNS groups and the western medicine treatment group presented an obvious role in relieving PF. We concluded that PNS could reduce the expression of AST, LDH, CK, IL-6, and IL-8 in serum of the rabbits, relieve the pathological ultrastructure of cardiopulmonary injury, alleviate PF. And it might be attributed to the inhibition on the NF-κB signaling pathway.