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Aims and Objectives: To investigate the factors associated with the exacerbations of COVID‐19. Background: At present, COVID‐19 is prevalent in the world, seriously endangering the property and life safety of people around the world. Currently, there are many reports on the clinical features, complications and risk factors of death of COVID‐19, but there are few reports on the factors associated with the exacerbation of COVID‐19. Design: Case–control Study. Methods: Patients with COVID‐19 were recruited from four designated hospitals for novel coronavirus pneumonia in Xiangyang City, Hubei Province from January to April 2020. The patients were divided into disease exacerbation group (n = 53) and disease stabilisation group (n = 265) according to the disease progression during hospitalisation. Univariate analysis and multivariate logistic regression were used to identify the factors associated with the exacerbation of COVID‐19. The research was reported according to STROBE statement. Results: Univariate analysis showed there were significant differences in gender, age, hypertension, heart disease, kidney disease, white blood cell count, percentage of neutrophil, percentage of lymphocyte, C‐reactive protein, lactate dehydrogenase, total protein, albumin, creatinine, calcium ion, rate of erythrocyte sedimentation, cough, expectoration, chest tightness, gastrointestinal discomfort and dyspnoea between the two groups. The variables with p < 0.05 in the aforementioned difference analysis were included in binary logistic regression analysis, which showed that age, hypertension history, chest tightness, percentage of neutrophil, percentage of lymphocyte, lactate dehydrogenase and creatinine were independent factors associated with COVID‐19 disease exacerbation. Conclusion: Clinicians may warn the exacerbation of COVID‐19 facing above risk factors and associated characteristics, and adjust the diagnosis and treatment plan to delay the disease progression, reduce complications and mortality and improve the prognosis of patients. Relevance to Clinical Practice: Patients with certain risk factors associated with COVID‐19 diseases exacerbation should be observed and targeted by using effective early interventions. [ABSTRACT FROM AUTHOR]