This study aims to investigate the therapeutic effects of Hippophae rhamnoides polysaccharide (HRP) on bleomycin-induced pulmonary fibrosis in mice and its underlying mechanisms. A total of 60 male BALB/c mice of SPF grade were randomly divided into six groups: control group, model group, positive drug pirfenidone group (6 mg/kg), and HRP low-dose group (100 mg/kg), HRP medium-dose group (200 mg/kg), HRP high-dose group (400 mg/kg), with ten mice in each group. A pulmonary fibrosis model was established via intratracheal aerosol inhalation. After the experiment, lung tissue samples were collected for histopathological examination, biochemical analysis, and gene and protein expression analysis. The results showed that compared with the model group, all HRP dose groups significantly improved pulmonary function parameters (P<0.05 or P<0.01), reduced the levels of inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 in lung tissues (P<0.05 or P<0.01), enhanced antioxidant capacity, increased the activity of superoxide dismutase (SOD) (P<0.05), decreased the content of malondialdehyde (MDA) (P<0.05 or P<0.01), and inhibited the expression of fibrosis markers in lung tissues (P<0.05 or P<0.01). Moreover, HRP significantly downregulated the expression levels of transforming growth factor-beta 1 (TGF-β1), TGF-β receptor I (TGF-βR1), phosphorylated Smad2 (p-Smad2), and phosphorylated Smad3 (p-Smad3) by modulating the TGF-β1/Smad signaling pathway (P<0.05 or P<0.01). This study provides scientific evidence for HRP as a potential natural anti-pulmonary fibrosis drug.