BACKGROUND: Qingre Sanjie Jiaonang (QRSJ) is a single herbal preparation from Senecio scandens Buch.-Ham.ex D. Don which has been proved to have anti-inflammatory and antioxidant effects. QRSJ has been used in treating upper respiratory tract inflammation and acute bronchitis in China for nearly twenty years. PURPOSE: This study aims to explore the potential effects of QRSJ in alleviating pulmonary fibrosis (PF) and its mechanisms. STUDY DESIGN AND METHOD: A mouse model of PF was induced by intratracheal injection of Bleomycin (BLM, 5 mg/kg), followed by different doses of QRSJ administration (0.5 g/kg, 1.0 g/kg) for 28 days. The lung tissues were collected and prepared for Hematoxylin-Eosin (H&E) staining to observe the pathological changes, while Masson staining was for determining collagen production. RNA sequencing (RNA-seq), flow cytometry and immunofluorescence experiments were employed to investigate the impact of QRSJ on the immune microenvironment. The expression levels of IL-1β, IL-6, CXCL15 (mouse homologue of human IL-8), and TNF-α in the bronchoalveolar lavage fluid (BALF) and serum of mice were observed. Besides, the levels of high mobility group protein B1 (HMGB1), an inflammatory and profibrotic mediator, in the BALF, serum and lung tissues of mice were also detected. RESULTS: The mouse model of PF was successfully established by checking the pathological examinations. With QRSJ intervention, BLM-induced destruction of alveolar structure and inflammatory cell infiltration were alleviated. H&E results further revealed that the administration of BLM and QRSJ had no impact on kidney histological structure of mice. Meanwhile, QRSJ inhibited the deposition of collagen, decreased the expression of fibronectin and lumican. Next, QRSJ treatment improved immune cell infiltration in the lung, along with the down-regulation of CD45 and Ly6G, and led to a decrease in the immune cell count in BALF. Furthermore, QRSJ alleviated the release of inflammatory factors, including NE, IL-1β, IL-6, CXCL15, and TNF-α. Besides, QRSJ significantly reduced the level of proinflammatory cytokine HMGB1. CONCLUSION: This study demonstrated the benefits of QRSJ in improving the pathological abnormalities in a PF model, revealing the new potential of the old drug. It should be attributed to the regulation of abnormal immune microenvironment and HMGB1 release. Future efforts should focus on its specific pharmacological mechanisms and clinical outcomes.