Objective: This study aims to evaluate the efficacy and safety of submucosal injection using a mixture containing sodium hyaluronate in submucosal tunneling endoscopic resection (STER) for esophageal submucosal tumors (SMTs). Methods: A total of 42 patients with SMTs participated in this study from January 2020 to October 2023. The patients were randomly divided into the experimental group (n=21) and the control group (n=21). The experimental group received a mixture of 5ml sodium hyaluronate injection (50mg) + 25ml fructose sodium chloride injection + 0.1ml methylene blue injection as submucosal injection. The control group received 30ml fructose sodium chloride injection + 0.1ml methylene blue injection. Submucosal injection started 5cm proximal to the SMT in the esophagus using the mixture until effective mucosal elevation for subsequent STER surgery. Results: There was no statistically significant difference in the average diameter of resected specimens between the experimental group (1.9±1.3 cm) and the control group (2.0±1.1cm, P>0.05). The average operation time in the experimental group (70.05±9.93 min) was significantly shorter than the control group (96.29±12.15 min, P<0.05). The average submucosal injection volume in the experimental group (13.52±2.77ml) was significantly lower than the control group (26.38±3.47ml, P<0.05). In cases with bleeding <5ml, the experimental group had 18 cases (86%), while the control group had 4 cases (19%); in cases with bleeding >5ml, the experimental group had 3 cases (14%), and the control group had 17 cases (81%), showing a statistically significant difference (P<0.05). Conclusion: Submucosal injection using a mixture containing sodium hyaluronate for STER surgery not only exhibits excellent efficacy but also high safety.