Objective To develop an animal model that replicates the clinical phenotype of severe asthma. Methods Ovalbumin (OVA) combined with IL-33 or varying doses of lipopolysaccharides ( LPS) was used to explore the construction of a severe asthma mouse model. Established model animals were assessed for lung function,number of inflammatory cells, and lung tissue pathology were assessed. Expression of key genes associated with severe asthma identified from the GEO database were validated in the new model. Results Compared with OVA alone,OVA combined with IL-33 or 5 μg LPS significantly increased airway resistance and the number of inflammatory cells in bronchoalveolar lavage fluid, and aggravated the pathological damage to lung tissues. The expression patterns of key genes in the newly constructed severe asthma models were consistent with those observed in clinical patients with severe asthma. Conclusions The modeling method of combining OVA with IL-33 or LPS (5 μg) can be used to construct experimentalanimal models of severe asthma.