Objective To compare the clinical efficacy of natural orifice specimen extraction surgery (NOSES) combined with enhanced recovery after surgery (ERAS) and conventional laparoscopic surgery in treatment of rectal cancer patients. Methods A hundred patients with rectal cancer in the Department of Colorectal and Anal Surgery, the 940th Hospital of Joint Logistics Support Force of PLA were selected as the research objects from January 2019 to December 2021, including 49 cases treated with NOSES combined with ERAS were set as the observation group, and 51 cases treated with conventional laparoscopic surgery of rectal cancer were set as the control group. Postoperative C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), white blood cell count (WBC), percentage of neutrophil (NEUT), K⁺ concentration, postoperative peristalsis recovery time, first time out-of-bed activity, first liquid feeding time, removal time of urinary, and drainage tubes, hospital stay and intraoperative blood loss, number of lymph node detection, positive margin rate, incidence of complications, and pain score were compared between the two groups. Results The observation group showed significant lower postoperative CRP, PCT, IL-6 levels when compared with control group(P<0.05), while no significant difference in K⁺ concentration between the two groups (P>0.05). The recovery time of intestinal peristalsis, the time of the first out-of-bed activity, the first liquid feeding time, the time of removal of the urinary tube and the drainage tube, and the number of days of hospitalization in observation group were all superior to the control group (P<0.05). The observation group with the duration of surgery was longer than the control group, and the difference was statistically significant (P<0.05). There were no significant differences in intraoperative bleeding, number of lymph nodes detected and positive rate of resection margins between the two groups (P>0.05). There was no significant difference in the incidence of complications between the two groups (4.1% vs. 7.8%, P>0.05). The observation group showed significant lower pain scores than control group on the 1st, 2nd and 3rd day after surgery (P<0.05). Conclusions NOSES combined with ERAS in treatment of rectal cancer patients is safe and feasible, can narrow the surgical incision, alleviate stress response and postoperative pain, improve postoperative efficacy and reduce the occurrence of complications, so is worthy of promotion and application.