Objective To study the effect of Qidong Huoxuefin combined with acetylcysteine on Pulmonary interstitial fibrosis (PIF). Methods From May 2021 to January 2023, 94 patients with PIF with Qi-yin deficiency and phlegm-stasis obstruction were selected as the study objects. The control group was treated with acetylcysteine effervescent tablets; The study group was treated with Qidong Huoxue decoction + acetylcysteine effervescent tablets. The clinical efficacy, pulmonary fibrosis [hyaluronic acid (HA), type III collagen (Ⅲ-C), laminin (LN), salivary glycoprotein 6 (KL-6)], chest HRCT score, cytokines [transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), interleukin-13 (IL-13), interferon gamma (INF-gamma)] and adverse reactions were analyzed and compared between the two groups. Results The total effective rate of the study group was significantly higher than that of the control group (P < 0.05). After treatment, the levels of HA, Ⅲ-C, LN and KL-6 in 2 groups were significantly lower than before treatment, and the study group was significantly lower than the control group (P < 0.05). There was no significant difference in the chest HRCT scores between the two groups before and after treatment (P > 0.05). After treatment, the levels of TGF-β, CTGF and IL-13 in both groups were significantly decreased compared with before treatment, and the levels of INF-γ were significantly increased compared with before treatment, and the change range of the study group was significantly greater than that of the control group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion Qidong Huoxueyin combined with acetylcysteine can improve the degree of pulmonary fibrosis in PIF patients, improve the therapeutic effect, improve the level of cytokines, and high safety.