AIM To evaluate the effectiveness and safety of submucosal tunneling endoscopic resection (STER) and compare its outcomes in esophageal and cardial submucosal tumors (SMTs) of the muscularis propria (MP) layer. METHODS From May 2012 to November 2017, 173 consecutive patients with upper gastrointestinal (GI) SMTs of the MP layer underwent STER. Overall, 165 patients were included, and 8 were excluded. The baseline characteristics of the patients and SMTs were recorded. The en bloc resection rate, complete resection rate, residual rate, and recurrence rate were calculated to evaluate the effectiveness of STER, and the complication rate was recorded to evaluate its safety. Effectiveness and safety outcomes were compared between esophageal and cardial SMTs. RESULTS One hundred and twelve men and 53 women with a mean age of 46.9 +/- 10.8 years were included. The mean tumor size was 22.6 +/- 13.6 mm. Eleven SMTs were located in the upper esophagus (6.7%), 49 in the middle esophagus (29.7%), 46 in the lower esophagus (27.9%), and 59 in the cardia (35.7%). Irregular lesions accounted for 48.5% of all lesions. STER achieved an en bloc resection rate of 78.7% (128/165) for GI SMTs with an overall complication rate of 21.2% (35/165). All complications resolved without intervention or were treated conservatively without the need for surgery. The en bloc resection rates of esophageal and cardial SMTs were 81.1% (86/106) and 72.1% (42/59), respectively (P = 0.142), and the complication rates were 19.8% (21/106) and 23.7% (14/59), respectively, (P = 0.555). The most common complications for esophageal SMTs were gas-related complications and fever, while mucosal injury was the most common for cardial SMTs. CONCLUSION STER is an effective and safe therapy for GI SMTs of the MP layer. Its effectiveness and safety are comparable between SMTs of the esophagus and cardia.