Objective To develop a stratified management model for postoperative sore throat (POST) in patients under general endotracheal anesthesia, and to explore the application effect. Methods A total of 266 patients were allocated into a control group of 142 and an intervention group of 126 chronologically. The control group was given usual care, while the intervention group received evidence-based stratified management protocol for POST. Results Compared with the control group, the incidence and severity of POST, as well as the incidence of adverse events were significantly lower, whereas the comfort score was significantly higher in the intervention group (all P<0.05). The timing of food intake was significantly earlier in the departments of spine surgery, gynecology, urology, and thoracic surgery in the intervention group than the control group (all P<0.05). Conclusion Evidence-based stratified management protocol for POST can reduce incidence and severity of POST in patients undergoing surgery under general endotracheal anesthesia, improve their comfort, and decrease adverse events.