In order to evaluate the efficacy and safety of submucosal tunneling endoscopic resection (STER) for the treatment of multiple submucosal tumors (SMT) in the upper gastrointestinal tract, data of 24 cases with upper gastrointestinal SMT (including 56 SMT lesions) treated at Taizhou Municipal Hospital and Shanghai East Hospital from January 2016 to June 2021 were collected for retrospective observation. The treatment effect, occurrence of major adverse events and follow-up results were analyzed. The results showed that 19 cases (79.2%) underwent tumor resection through one tunnel, and 5 cases (20.8%) underwent tumor resection through two tunnels. The length of the tunnel was 3-12 cm, with an average of 6.2 cm. The surgical time ranged from 19 to 130 minutes, with an average of 55.6 minutes. The overall resection rate was 89.29% (50/56). The hospitalization time was 2-7 days, with an average of 3.5 days. Major adverse events occurred in 2 cases (8.3%), all of which were mucosal injuries, and were cured with titanium clips and self expanding metal sealing stents. During a follow-up period of 6-64 months, with an average of 32.0 months, there was no residual tumor, tumor implantation tunnel, local recurrence, distant metastasis or death. To sum up, STER is safe and feasible for the treatment of multiple SMT in the upper gastrointestinal tract. The main resection method is single tunnel, and double tunnel is required for multiple SMT far apart.