OBJECTIVE To evaluate the effectiveness and safety of S-ketamine for pain relief and analgesic consumption in surgical patients. METHODS Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS Perioperative setting. METHODS A total of 905 adult patients undergoing surgery using general anesthesia: 504 patients in the S-ketamine group and 401 patients in the placebo group. METHODS Intravenous S-ketamine as an adjuvant to general anesthesia compared with placebo. METHODS The primary outcomes were resting and movement pain scores (VAS/NRS 0-10) and morphine consumption within 4, 12, 24 and 48 h after surgery. The secondary outcomes included postoperative complications such as nausea, vomiting, and psychotomimetic adverse events. We used the guidelines of the Recommendation Assessment, Development, and Evaluation (GRADE) system to evaluate the level of certainty for the main results. RESULTS A total of 12 studies were included. The types of surgery included abdominal surgery, thoracotomy, gynecologic surgery, arthroscopic anterior cruciate ligament repair, cardiac surgery, laparoscopic cholecystectomy, lumbar spinal fusion surgery, radical prostatectomy, and hemorrhoidectomy. There were significant improvements in resting pain scores at 4, 12 and 24 h with S-ketamine versus placebo [4 h: standardized mean difference (SMD) -1.11; 95% confidence interval (CI): -1.53, -0.68, p < 0.00001; GRADE = moderate; 12 h: SMD -0.88; 95%CI: -1.42, -0.34, p = 0.001; GRADE = moderate; 24 h: SMD -0.39; 95%CI: -0.73, -0.06, p = 0.02; GRADE = moderate]. The incidence of pain scores at 48 h showed no statistical difference between the two groups (SMD -0.27; 95%CI: -1.12, 0.58, p = 0.53, GRADE = moderate). The movement pain scores were not significantly different between the two groups at each time point (4 h: SMD -0.34; 95%CI: -0.73, 0.05, p = 0.09, GRADE = moderate; 12 h: SMD -0.42; 95%CI: -1.46, 0.63, p = 0.44, GRADE = low; 24 h: SMD -0.58; 95%CI: -1.25, 0.09, p = 0.09, GRADE = moderate; 48 h: SMD -0.49; 95%CI: -1.11, 0.14, p = 0.13, GRADE = low). At 4 and 12 h after surgery, the consumption of morphine was significantly reduced in the S-ketamine group (4 h: SMD -0.98; 95%CI: -1.37, -0.06, p < 0.00001, GRADE = moderate; 12 h: SMD -1.36; 95%CI: -2.26, -0.46, p = 0.003, GRADE = low). There were no significant differences in morphine use at 24 and 48 h between the two groups (24 h: SMD -0.70; 95%CI: -1.42, 0.02, p = 0.06, GRADE = low; 48 h: SMD -0.79; 95%CI: -2.26, 1.03, p = 0.39, GRADE = low). The risk for nausea [relative risk (RR) = 1.04; 95%CI: 0.83, 1.30, p = 0.73], vomiting (RR = 1.07; 95%CI: 0.84, 1.38, p = 0.57), and psychotomimetic adverse events (RR = 1.57; 95%CI: 0.82, 2.99, p = 0.17) showed no significant increase in the S-ketamine group. CONCLUSIONS Intravenous S-ketamine as an adjunct to general anesthesia is effective for assisting analgesia and decreases the intensity of pain and opioid requirements in a short period of time after surgery, but it may increase the psychotomimetic adverse event rate. Overall, the level of certainty is moderate to low.