Objective To explore the practice and significance of cluster nursing strategy in the safety management of patients undergoing painless gastroscopy. Methods 692 patients who underwent painless gastroenteroscopy in the digestive endoscopy center of a tertiary hospital in Shanghai from October 2017 to October 2018 were randomly divided into two groups. 328 patients in the control group were treated with routine nursing and 365 patients in the observation group were treated with cluster nursing strategy. The standard rates of fasting and water prohibition, the quality of intestinal preparation and the incidence of intraoperative adverse events were compared and analyzed. Results The standard rates of fasting and water prohibition and the incidence of intraoperative adverse events in the observation group were significantly lower than those in the control group (P < 0.05). The intestinal preparation in the observation group was better than that in the control group (P < 0.05). Conclusion The cluster nursing strategy for painless gastroscope combined examination is helpful to ensure the safety of patients, improve the quality of intestinal preparation, reduce the incidence of adverse events and improve the quality of medical and nursing service.