Signal transducer and activator of transcription protein 3 (STAT3), one of the major regulators of inflammation, plays multiple roles in cellular transcription, differentiation, proliferation, and survival in human diseases. Dysregulation of STAT3 is related to the severe airway inflammation associated with asthma. FLLL31 is a newly developed compound based on the herbal medicine curcumin, which specifically suppresses the activation of STAT3. However, the function of FLLL31 on inflammatory diseases, especially on the regulation of airway inflammation, has not been fully studied. In our prior investigations, we developed a mouse model that was challenged with a mixture of DRA allergens (including house dust mite, ragweed, and Aspergillums species) to mimic the severe airway inflammation observed in human patients. In this study, we performed a series of experiments on the inflammatory regulation activities of FLLL31 in both in vitro cultured cells and our in vivo DRA-challenged mouse model. Our results show that FLLL31 exhibits anti-inflammatory effects on macrophage activation, lymphocyte differentiation, and pro-inflammatory factor production. Importantly, FLLL31 significantly inhibited airway inflammation and recruitment of inflammatory cells in the DRA-challenged mouse model. Based on these results, we conclude that FLLL31 is a potential therapeutic agent that can be used against severe airway inflammation diseases.