AIM: To investigate the impact of esketamine-mediated opioid-free anesthesia (OFA) on postoperative gastrointestinal function in patients undergoing laparoscopic distal gastrectomy for gastric cancer. METHODS: A total of 150 patients, scheduled for elective laparoscopic distal gastrectomy for gastric cancer and meeting the inclusion and exclusion criteria, were randomly assigned to either the OFA group or the opioid-based anesthesia (OBA) group using a random number table,?with 75 patients in each group. The OFA group was administered an anesthesia regimen primarily consisting of esketamine, while the OBA group received conventional opioid anesthesia, primarily consisting of sufentanil and remifentanil. The primary outcome measure was postoperative flatus time, defined as the interval from the end of surgery to the first passage of gas. RESULTS: The OFA group exhibited a shorter postoperative flatus time compared to the OBA group (P<0.01). Intraoperative blood loss and norepinephrine consumption were significantly less in the OFA group compared to the OBA group (P<0.05); the postoperative HADS-D score was better in the OFA group than in the OBA group, and both the OFA and OBA groups showed significantly lower postoperative HADS-A and HADS-D scores compared to their preoperative levels (P<0.05); the incidence rate of abdominal distension was significantly lower in the OFA group compared to the OBA group (P<0.05). CONCLUSION: The use of esketamine-mediated opioid-free anesthesia can expedite gastrointestinal function recovery, reduce hospital stay duration, and decrease postoperative adverse reactions in patients undergoing laparoscopic distal gastrectomy for gastric cancer.