OBJECTIVES: To establish a system for control of cross-infection and workflow for preventing severe acute respiratory syndrome coronavirus 2 spread and ensuring the safety of medical staffs and patients in endoscopy center during the pandemic of the coronavirus disease 2019 (COVID-19). METHODS: Based on the national publication of relevant documents and relevant guidance of Digestive Endoscopy Branch of Chinese Medical Association, we explored and optimized the workflow, staff protection and sterilization of endoscope in digestive endoscopy center during the pandemic of the COVID-19. RESULTS: The prevention system of cross-infection and workflow in endoscopy during the pandemic of the COVID-19 were developed. The optimized workflow in endoscopy was conducted in 106 patients with necessary endoscopy from the Department of Gastroenterology, Third Xiangya Hospital, Central South University between January 24, 2020 and February 26, 2020, and no case of cross-infection was presented among the medical staffs, patients and family members. CONCLUSIONS: Measures on control of cross-infection and workflow in digestive endoscopy center during the pandemic of the COVID-19 are effective, which are beneficial to preventing cross-infection in hospital and provide a scientific guidance for the general work in the digestive endoscopy centers during the pandemic of the COVID-19.