Objective To explore the rule of traditional Chinese medicine (TCM) syndrome differentiation of coronavirus disease 2019 (COVID-19) patients. Methods The symptoms of 756 cases with COVID-19 in Guanggu Branch of Maternity and Child Healthcare Hospital of Hubei Province were collected by cross sectional survey. The incidence rates of the symptoms were recorded by frequency method at different courses of the disease:prodromal stage (onset), middle stage (7-30 days), and later stage (>30 days). The common symptoms (incidence rate>5.0%) were analyzed by systematic clustering. With expert experience, the rule of TCM syndrome differentiation of COVID-19 patients was summarized. Results Fever (52.25%, 395 cases), cough (43.25%, 327 cases), asthenia (27.25%, 206 cases), chest distress (26.72%, 202 cases), asthma (17.59%, 133 cases) and expectoration (5.03%, 38 cases) were the most common symptoms in the prodromal stage (756 cases) of the disease, which were clustered into one category except expectoration, indicating the pathogenesis of both lung and body surface suppressed by dampness. In the middle stage (383 cases), the 19 common symptoms including greasy fur (64.49%, 247 cases), yellow fur (43.86%, 168 cases), thick fur (40.21%, 154 cases), cough (34.73%, 133 cases), red tongue (32.38%, 124 cases), poor stool (25.85%, 99 cases), asthma (25.33%, 97 cases), asthenia (25.07%, 96 cases), poor appetite (23.76%, 91 cases), bitterness of mouth (14.36%, 55 cases), dry fur (12.01%, 46 cases), purple tongue (12.01%, 46 cases), perspiration (11.49%, 44 cases), constipation (10.18%, 39 cases), white phlegm (8.62%, 33 cases), insomnia (7.31%, 28 cases), nausea (7.05%, 27 cases), diarrhea (6.79%, 26 cases) and yellow phlegm (6.27%, 24 cases), were clustered into three groups, indicating the pathogenesis of damp-heat accumulation, obstruction of lung and spleen by dampness, and dryness due to dampness-heat. In the later stage (373 cases), the 13 common symptoms including greasy fur (50.94%, 190 cases), asthenia (39.41%, 147 cases), cough (37.80%, 141 cases), red tongue (33.78%, 126 cases), asthma (32.17%, 120 cases), perspiration (23.86%, 89 cases), dry mouth (22.79%, 85 cases), poor appetite (20.11%, 75 cases), poor stool (19.30%, 72 cases), bitterness of mouth (15.01%, 56 cases), white phlegm (10.72%, 40 cases), palpitation (8.31%, 31 cases) and little fur (8.04%, 30 cases), were clustered into two groups, indicating the pathogenesis of deficiency of Qi and Yin with residual dampness, and deficiency of lung Qi and spleen Qi with residual dampness. Conclusion The TCM syndromes of COVID-19 patients in different stages have its own typical characteristics, with a regular change from exterior to interior, from dampness to dampness-heat and from excess to deficiency.