Objective. To analyze the efficacy and safety of submucosal tunnel endoscopic resection (STER) for the treatment of submucosal masses in esophageal muscularis propria. Method. A total of 272 patients with submucosal masses in esophageal muscularis propria diagnosed and treated in our hospital from February 2019 to January 2022 were randomly selected for the study and then were randomly divided into the STER group ( n = 136 ) and the endoscopic mucosal dissection (ESD) group ( n = 136 ) according to the random number table method. Patients in the STER and ESD groups were treated with STER and ESD, respectively. The clinical data of patients from the two groups were collected and compared. The clinical effects and the changes of surgery-related indexes of patients after ESD and STER treatment were observed. The safety of ESD and STER was compared. The factors influencing the efficacy of STER treatment for submucosal masses in esophageal muscularis propria were analyzed. Result. There were significant differences between the STER group and the ESD group in terms of tumor size, lesion level, adhesion and surgical approaches ( P < 0.05 ). The effective rates of ESD treatment and STER treatment were 98.53% and 88.97%, respectively. Meanwhile, the effective rates of STER treatment were significantly higher than those in the control group ( P < 0.05 ). In addition, the patients in the STER group had longer operation time, less blood loss, and shorter hospital stay compared with those in the ESD group ( P < 0.05 ). Adverse reactions occurred during ESD treatment and STER treatment included delayed bleeding, adhesion, perforation, and pleural effusion with the total incidence of adverse reactions of 4.41% and 13.97%, respectively. The adverse reactions in STER group were prominently less than these in the ESD group ( P < 0.05 ). Logistic multivariate regression analysis showed that independent risk factors, including tumor size, lesion level, adhesion, and surgical approaches, affected the efficacy of STER in the treatment of submucosal masses in esophageal muscularis propria ( P < 0.05 ). Conclusion. STER is an effective method for the treatment of submucosal masses in esophageal muscularis propria, which can exhibit a good effect with faster postoperative recovery and higher safety, thereby being worthy of clinical application and promotion. Tumor size, lesion level, adhesion, and surgical approaches are all related factors affecting the effect of STER treatment.