BACKGROUND: Physochlainae Radix (PR), a valuable traditional Chinese medicine, has been historically applied for the treatment of bronchitis and asthma in clinic, yet its mechanisms have not been clearly elucidated. PURPOSE: This study aims to reveal the underlying mechanisms of PR in treating asthma, employing transcriptomics and network pharmacology approaches. METHODS: To evaluate the therapeutic effects of PR on asthma, we established the asthmatic model in ICR mice by using OVA. Firstly, we employed LC-MS and GNPS to analyze the major chemical constituents in PR. Subsequently, the effects of PR in asthma treatment were assessed through histology, biochemical analysis, and immunofluorescence (IF) assay. Further, an integrated approach of transcriptomics and network pharmacology was applied to identify the target proteins and related pathways of PR against asthma. IF, immunohistochemical (IHC), enzyme-linked immunosorbent assay (ELISA), and western blotting (WB) were utilized for experimental validation and mechanistic studies. RESULTS: Using UPLC/Q-Orbitrap-MS and GNPS, we eventually identified 23 potential active components from PR. It was discovered for the first time that PR contains a large number of steroidal saponins. PR treatment has been shown to improve lung function, histomorphological changes, and inflammation in the OVA-induced asthma model. According to the results of the transcriptomics and network pharmacology research, PR targeted CXCR2, CCR1, MMP3, MMP9, and IL-17 as crucial elements for treating asthma through the TLR4/MyD88/NF-κB, MAPK, and IL-17 pathways. The key proteins of these pathways were validated by IF and/or WB. Additionally, it was verified that the therapeutic effect of PR on asthmatic mice was related to the inhibition of the activation of the TLR4/MyD88 pathway by introducing TAK-242, an inhibitor of TLR4. CONCLUSIONS: This research revealed that PR improves asthma through the TLR4/MyD88/NF-κB, MAPK, and IL-17 pathways. It is worth noting that this is the first time that transcriptomics and network pharmacology have been comprehensively used to explore the mechanism of PR in treating asthma. This finding advances our understanding of the pharmacological mechanisms underlying PR and lends support to its usage as a treatment agent for asthma.