Abstract: Objective This study establishes a model of invasive Aspergillus niger lung disease in immunosuppressed rats to provide theoretical support for the pharmacodynamic evaluation of anti-invasive pulmonary aspergillosis drugs and mechanism studies. Methods Sixty SD rats were randomly divided into a normal control group, a cyclophosphamide control group, and a cyclophosphamide + fungal infection low, medium, and high dose group, with 12 animals in each group. General clinical observations were performed daily, and the serum levels of immunoglobulin G (IgG), immunoglobulin M (IgM) and serum galactomannan (GM) were detected by ELISA on the 3rd and 7th days of modeling, respectively, as well as the ratio of CD4+ and CD8+ cells and the content of white blood cells (WBCs) and neutrophils (Neu) in peripheral blood, and the load of Aspergillus niger in alveolar lavage were observed simultaneously and morphological changes of rat lung tissue. Results The rats in the cyclophosphamide control group and the cyclophosphamide+fungal infection group showed reduced voluntary activity and erect hair after modeling, and the rats in the cyclophosphamide+fungal infection group were accompanied by shortness of breath and audible wet rhonchi in the lungs; compared with the normal control group, the rats in the cyclophosphamide control group showed significant reductions in the levels of CD4+, WBC, Neu, IgG and IgM in the blood, and the proportion of CD8+ was significantly higher (P<0.05, P<0.01); compared with the cyclophosphamide control group, rats in the cyclophosphamide+fungal infection group showed significant decreases in blood levels of CD4+, WBC, Neu, IgG, IgM, and significant increases in levels of CD8+, GM, and the alveolar lavage load of Aspergillus niger (P<0.05, P<0.01); and the lung tissues of the cyclophosphamide+fungal infection rats in the low-, medium-, and high-dose groups showed mycelial distribution and destruction of alveolar epithelium, increase of bronchial epithelial cup cells in the alveoli, and infiltration of inflammatory cells, and the degree of lesions was positively correlated with the modeling dose. Conclusion In this study, we used Aspergillus niger combined with cyclophosphamide immunosuppressant to construct a model of invasive Aspergillus niger lung disease, and the duration of the disease was positively correlated with the concentration of the bacterial fluid and the modeling time, which confirms that the cellular immunity plays an important role in the pathogenesis of the disease, and at the same time the immunoglobulin can also affect the development of the disease process of invasive pulmonary aspergillosis, and it is speculated that the pathogenesis of invasive pulmonary aspergillosis may be related to the level of immunoglobulin in the humoral immunity.