Purpose: To investigate the therapeutic effects of saikosapoin D (SSD) on bleomycin (BLM)-induced pulmonary fibrosis (PF) in mice and its probable mechanisms. Methods: PF mice were prepared by intraperitoneal (i.p.) injection of BLM (5 mg/kg). Twenty-four hours later, 72 mice in SSD group were administered SSD (1.8 mg/kg, ip). After 3, 7, 14 and 28 days of injection, the mice were sacrificed. Blood samples and lung tissues were collected from 6 mice in each group. The lung tissues were subjected to histological examination. In addition, expressions of MyD88, TRAF6, IL-33 and ST2 in lung tissue were determined by western blotting assay. Serum levels of hydroxyproline (HYP), interleukin (IL)-4, IL-13 and interferon (IFN)-y were measured by enzyme-linked immunosorbent assay (ELISA). Results: Pathological results showed that SSD treatment alleviated alveolitis and lung fibrosis (p < 0.05) in lung tissues of PF mice at 14 and 28 days post-BLM injection. HYP and IL-13 levels of mice in SSD group were significantly lower than that in BLM group at days 14 and 28 post-BLM injection (p < 0.05). Levels of IL-4 and IFN-y were significantly lower when compared with values in BLM group on day 28 (p < 0.05). Western blotting results revealed that expressions of MyD88, TRAF6, IL-33 and ST2 proteins were significantly decreased by SSD treatment (p < 0.05). Conclusion: SSD exerts therapeutic effects on BLM-induced experimental PF in mice via regulation of IL-33/ST2 pathway.