Objective To establish a disease-syndrome combination model of human coronavirus 229E ( hCoV- 229E) pneumonia and “Hanshi Yidu Xifei” syndrome, observe the consistency of traditional Chinese medicine syndrome and the disease of the model with typical clinical manifestations of viral pneumonia, and verify the reliability of the model for pharmacodynamic evaluation. Methods Young BALB/ c mice were placed in a cold damp environment and infected with hCoV-229E to establish the mouse model. The appearance and behavior of model mice, serum gastrointestinal hormone levels, lung index, viral load in lung tissue, changes in the presence of live virus, lung histopathology and imaging, inflammatory cytokines, and lymphocytes in peripheral blood were analyzed. A Chinese herbal compound prescription for “Hanshi Yidu Xifei” syndrome was used to assess the reliability of the model for drug evaluation. Results Compared with normal mice, model mice showed the appearance and behaviors of cold-dampness syndrome, such as reduced food and water intake, loose stool and greasy hair (P<0.05 or P<0.01). An increased motilin level (P<0.01) and decreased gastrin level (P<0.01) were also found in model mice. Viral nucleic acids in lungs, an increased lung index (P<0.01), increased lung and bronchial histopathology scores (P<0.05 or P<0.01), reduced frequency of T and B lymphocytes (P<0.01), and increased levels of inflammatory cytokines (P< 0.01) were also observed, which were similar to the clinical features of coronavirus pneumonia. The prescription was effective to reverse the changes in these indicators (P< 0.05 or P<0. 01). Conclusions The disease-syndrome combination model of hCoV-229E pneumonia and “Hanshi Yidu Xifei” syndrome was established successfully and consistent with clinical manifestations. It provides a potential tool for drug screening to treat pneumonia presenting with this traditional Chinese medicine syndrome.