BackgroundPulmonary fibrosis (PF) is a chronic and potentially fatal lung disease and disorder. Although the active ingredients of ginseng honeysuckle superfine powdered tea (GHSPT) have been proven to have anti-inflammatory and antioxidant effects, the mechanism of GHSPT on PF remains unclear. The present study was to explore the underlying mechanism of GHSPT in treating PF based on proteomics and network pharmacology analysis and to confirm it in vivo.Materials and methodsWe used intratracheal instillation of bleomycin to induce the PF mouse model and GHSPT (640 mg/kg) intragastrically administrated to PF mice for 21 days. The lung tissues were harvested for TMT-based proteomics. The UPLC-Q-Exactive MS/MS analyze the serum migrant compounds of GHSPT in the PF mice. Moreover, components of GHSPT were harvested from the pharmacology database of the TCMSP system. PF-related targets were retrieved using NCBI and GeneCards databases.ResultsOur results showed that GHSPT significantly alleviated PF mice. Proteomics analysis showed that 525 proteins had significantly changed in the lung of untreated PF mice. Among them, 19 differential proteins were back-regulated to normal levels after GHSPT therapy. Moreover, 25 compounds originating from GHSPT were identified in the serum sample. Network analysis showed 159 active ingredients and 92 drug targets against PF. The signaling pathways include apoptosis, ferroptosis, cytokine-cytokine receptor, P53, and PI3K-Akt signaling pathway.ConclusionThe evidence suggests that GHSPT might play an effective role in the treatment of PF by multi-target interventions against multiple signaling pathways.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13020-023-00769-x.