Purpose: To discuss the effects and mechanisms of improvement of Hydroxysafflor yellow A in pulmonary fibrosis by in vivo study. Material and Methods: In this study, dividing the C57BL/6 mice as 4 group, there were 10 mice in every group. Collecting the serum of difference groups and measuring the Hyp, SOD, MDA, TNF-α and IL-6 levels. Lung tissues were taken out and evaluating the pathology by HE staining and fibrosis degree by Masson staining. The relative proteins (α-SMA and E-cadherin) were measured by IHC and WB in lung tissues of difference groups. Results: With HSYA or DXM supplement, the Hyp, MDA, TNF-α and IL-6 concentrations significantly suppressed and SOD concentration significantly enhanced (P < 0.05, respectively). Compared with Sham group, the pathology injury and fibrosis degree of Model group were significantly up-regulation (P < 0.001, respectively); With HSYA or DXM treatment, the pathology injury and fibrosis degree of HSYA and DXM groups were significantly improved (P < 0.05, respectively). By IHC and WB assay, the α-SMA and E-cadherin proteins expressions of Model group were significantly differences (P < 0.001, respectively); however, the α-SMA and E-cadherin proteins expressions of HSYA and DXM groups were significantly improved with HSYA or DXM supplement (P < 0.05, respectively). Conclusion: HSYA improves pulmonary fibrosis by regulation α-SMA and E-cadherin in vivo study.