Objective To compare and analyze the differences and characteristics of three strain mouse models infected by influenza virus aerosol inhalation, and provide the reference for choosing the appropriate infection model in the research of pathogenesis of influenza and the development of vaccines and drugs. Method C57BL/6, BALB/c and ICR mice were infected with A/Puerto Rico/8/34 (H1N1) virus strain by aerosol inhalation. The symptoms and body weight of mice were observed every day. At 3, 7, 14 days after infection, the mice were sacrificed. The lungs of mice were weighed, then virus assay and pathological observation were carried out. Results The three strains of mice were infected. The survival rate in the C57BL/6 mice was lower than those in the BALB/c and ICR mice. The lung index and viral load of C57BL/6 mice were significantly higher than those of ICR mice (P<0.05) at 3 days after infection. The pathological changes of C57BL/6 mice were also more obvious than other two strains. Compared with other two mouse strains, the weight recovery of BALB/c mice was the slowest. The survival rate in BALB/c mice was higher than that of C57BL/6 mice and lower than that of ICR mice. The lung index and viral load were not significantly different among the three strains of infected mice. The pathological changes among the three strains of infected mice were similar, but the degrees of pathological changes in the BALB/c mice were milder than in the C57BL/6 mice and worse than in the ICR mice. Compared with other two mouse strains, the process of disease is similar, but the body weight, mortality, lung index, viral load, and the microscopic pathological changes were lighter in the ICR mice than in the other two strain mice. Conclusions The three strain mouse models can be established by influenza virus aerosol inhalation, but showing different characteristics. Appropriate strain mice can be chosen to build model according to different research purpose in the experiment.