Single-port access (SPA) laparoscopic surgery and vaginal natural orifice transluminal endoscopic surgery (vNOTES) have many advantages. The objective of the present study is to compare patient characteristics, operative details, and postoperative outcomes between the two surgical methods. Patients who were planned to undergo vNOTES or SPA laparoscopic surgery between April 2020 and June 2021 were prospectively enrolled. The surgical method was determined by a single surgeon after imaging results evaluation and a physical exam. Those who had favorable pelvic conditions without any evidence of adhesion were scheduled for vNOTES. A total of 33 patients underwent a vNOTES hysterectomy while 40 patients received a SPA laparoscopic hysterectomy. All surgeries were performed by one surgeon. The proportion of the patients who had a history of vaginal delivery was significantly higher in the vNOTES group. The operative time for port installation was significantly longer in the vNOTES group, but the total operative time was shorter compared to the SPA group. The postoperative pain scores 12 h after the operations were also significantly lower in the vNOTES group. Other surgical outcomes were comparable between the two groups. The present study demonstrated that the early operative outcomes of vNOTES hysterectomy were comparable to those of SPA hysterectomy. It also highlights the importance of adequate patient selection when determining surgical methods based on imaging results and physical examinations.