Objective To establish a reasonable and practical pathological mouse model for the attribution of coronavirus disease 2019 (COVID-19) as “ cold-dampness epidemic” under the theory of Traditional Chinese Medicine (TCM). Methods Twenty-four male KM mice were randomly divided into three groups: normal group and two model groups. The mice in model group 1 (lipopolysaccharide [LPS] group) were intraperitoneally injected with 5 mg / kg of LPS saline solution, those in model group 2 (“ LPS + cold-dampness stimulation” syndrome group) were intraperitoneally injected with 5 mg / kg of LPS saline solution and cold dampness stimulation, and those in the normal group were injected with the same amount of normal saline. After 8 days, the appearance and behavior of model mice were evaluated under the theory of TCM; additionally, the lung index, spleen index, and thymus index were evaluated, and the levels of inflammatory factors in the lung tissues were detected by ELISA, and the protein expression levels of COX-2, TRPV1 and TRPA1 were detected. Results Mice in the LPS + “cold-dampness stimulation” syndrome group exhibited an appearance and behavior similar to those of cold-dampness syndrome, e. g. , decreased activity and poor mental state. The lung index, thymus index, and spleen index of model groups were higher than those of the normal group. The levels of TNF-α, IFN-γ, IL-6 and PGE2 in the LPS + “ cold-dampness stimulation” syndrome group were significantly higher than those in the normal group or the LPS group. HE staining revealed that the extent of injury in the model groups were more severe than that in the normal group. The expression levels of COX-2 and TRPA1 protein were significantly higher in the model groups, whereas the expression level of TRPV1 protein was significantly lower. Conclusions The LPS + “ cold-dampness stimulation” syndrome mouse model can be used as an ideal method to construct the syndrome of “HanShiYi” caused by COVID-19 under the theory of TCM, and the changes of indexes of mice in the LPS + “ cold-dampness stimulation” syndrome model group are consistent with the body damage caused by COVID-19 reported in the literature.