ETHNOPHARMACOLOGICAL RELEVANCE: Asthma is a chronic inflammatory disease, characterized by airway inflammation, hyperresponsiveness, and bronchial smooth muscle contraction. Qingfei Xiaoyan Wan (QFXYW), a traditional Chinese formula, has been shown to exert anti-asthma effects and immune response in multiple diseases. AIM OF THIS STUDY: In this study, we evaluated the therapeutic mechanism of QFXYW in the suppression of allergic asthma by integrating of transcriptomics and system pharmacology. MATERIALS AND METHODS: BALB/c mice were sensitized with ovalbumin (OVA) to establish the allergic asthma model, and its success was confirmed with behavioral observations. Lung histopathological analysis, inflammatory pathology scores, transcription factors were used to evaluate the effects of QFXYW on allergic asthma. The therapeutic mechanism of QFXYW in treating allergic asthma through integrated transcriptomics and system pharmacology was then determined: hub genes were screened out by topological analysis and functional enrichment analysis were performed to identify key signaling pathway. Subsequently, quantitative RP-PCR and protein array were performed to detect the mRNA of hub genes and to predict the key pathway in OVA-induced allergic asthma, respectively. RESULTS: Our results demonstrated that QFXYW could significantly attenuate inflammatory cell infiltration, mucus secretion, and epithelial damage. The transcriptomics analysis found the six hub genes with the highest values- CXCL10, CXCL2, CXCL1, IL-6, CCL-5, and CCL-4 were screened out. Functional enrichment analysis showed that the differentially expressed genes (DEGs) were mainly enriched in the inflammatory response and cytokine signaling pathway. Moreover, the quantitative RT-PCR verification experiment found the CXCL2 and CXCL1 were significantly suppressed after treatment with QFXYW. The results of protein array showed that QFXYW inhibited the multi-cytokines of OVA-induced allergic asthma via cytokine signaling pathway. CONCLUSIONS: QFXYW may have mediated OVA-induced allergic asthma mainly through the hub genes CXCL2, CXCL1, and the cytokine signaling pathway. This finding will offer a novel strategy to explore effective and safe mechanism of Traditional Chinese Medicine (TCM) formula to treat allergic asthma.