Objectives: Transoral thyroidectomy is becoming a preferred technique because it has the advantage of not leaving a scar after surgery. However, it’s not yet standard because of the anatomic nerve complexity of this oral cavity and difficulty of approach. The aim of this study was to determine the safety zone of a gasless transoral thyroidectomy approach using an anatomical study and to evaluate the efficacy of this approach on clinical application. Methods:Phase 1, twenty unilateral specimens from fresh cadavers underwent staining by the modified Sihler’s method to identify nerves around the oral vestibules. Then, the safety zone of the transoral thyroidectomy approach was proposed. Phase 2, a comparative analysis of the clinical outcomes of gasless transoral thyroidectomy through the safety zone versus transcutaneous thyroidectomy approach. Result:In phase 1, numerous inferior labial branches diverged from the mental nerve and were distributed across the lower lip. In most cases, the most lateral branch reached almost to the corner of the mouth, whereas a nerve-free area was present at the medial region of the lower lip. The suggested safety zone was presented as a trapezoid shape. In phase 2, there were no significant differences in age, mass size, or complications between the two groups. However, the operation time in the transoral thyroidectomy group was longer than in the transcutaneous group (p = 0.001). Conclusion:Based on the anatomical study, we suggested a safety zone for the gasless transoral thyroidectomy. On application of this safety zone, gasless transoral thyroidectomy is a safe and feasible procedure.