Ethnopharrnacological relevance: Nowadays, bronchial asthma is still a severe disease threatening human health, and it is incumbent upon us to seek effective therapeutic drugs. Mahuang decoction (MHD), a classic famous Chinese prescription, has been used for thousands of years to prevent phlegm from forming, stop coughing and relieve asthma, but the relevant mechanism has not been thoroughly clarified. This study aims to investigate the anti-airway inflammation effect of MHD and the possible molecular mechanism underlying IL21/STAT3 signaling pathway, so as to provide guidance for the treatment of MHD on bronchial asthma. Materials and methods: Specific pathogen free SD rats were randomly divided into 6 groups: normal control group, model group, positive group (Compound methoxyphenamine), MHD-treated groups at doses of 10 ml/kg, 5 ml/kg and 2.5 ml/kg, 10 rats in each group. Except for the normal control group, rats in other groups were sensitized with ovalbumin via introperitoneal injection and challenged with ovalbumin inhalation to trigger asthma model. At 24 h after the last excitation, bronchoalveolar lavage fluid (BALF) of every rat was drawn and the number of inflammatory cells was analyzed using cell counting method. ELISA method was performed to determine the concentrations of TXB2, 6-keto-PGF(1 alpha) MMP-9, TIMP-1, IL-2, IL-4, IL-5 and TNF-alpha in rat serum. The protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in murine pulmonary tissues were assessed with western blotting analysis. Results: Compared with the control group, the airway wall and airway smooth muscle of murine pulmonary tissues significantly thickened and massive inflammatory cells infiltration occurred around the bronchus in the model group, and the cell counts of WBC and EOS in BALF were also apparently increased, which indicated the rat asthma model was successfully established. MHD or Compound methoxyphenamine not only alleviated the pulmonary inflammatory pathological damages, but also down- regulated the numbers of WBC and EOS in BALF. What's more, the levels of TXB2, MMP-9, TIMP-1, ILs-(2, 4, 5) and TNF-a in rat serum were lessened by the treatment of MHD. In western blotting analysis, treatment with 10 ml/kg or 5 ml/kg MHD markedly declined the increased protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in lung tissues of asthmatic rats to normal level. Conclusion: MHD intervention demonstrated a strong inhibitory action on the secretion of inflammatory mediators as well as the inflammatory cell infiltration in pulmonary tissues of asthmatic rats, and also depressed the protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in pulmonary tissues. MHD effectively mitigates airway inflammation and regulates the IL-21/STAT3 signaling pathway in rat asthma model.