Aim: We aimed to assess the beneficial and harmful effects of perioperative pain treatment with ketamine in patients undergoing spinal surgery. Methods: We searched Medline, Embase, and CENTRAL from inception until 15 February 2023 for randomised clinical trials comparing ketamine with placebo or no intervention in patients undergoing spinal surgery. The primary outcomes were cumulative opioid consumption at 24 h postoperatively and serious adverse events. We adhered to recommendations of the Cochrane Collaboration and performed meta-analysis, Trial Sequential Analysis (TSA) to assess the risks of random errors, risk of bias assessment to evaluate the risks of systematic errors, and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We included a total of 28 randomised clinical trials enrolling 2110 participants providing data for our pre-defined outcomes. Twenty-three trials enrolled adult participants and 5 trials enrolled paediatric participants. Three trials were at low risk of bias. Meta-analysis and TSA of trials including adults showed that ketamine versus placebo or no intervention seemed to reduce the cumulative 24-h opioid consumption (mean difference −17.57 mg; TSA-adjusted 95% confidence interval, −24.22 to −10.92; p <.01; low certainty of evidence), and there was no evidence of a difference of ketamine versus placebo or no intervention on the risk of serious adverse events (risk ratio 2.16; 96.7% confidence interval, 0.35 to 13.17; p =.36; very low certainty of evidence). Conclusion: In adults undergoing spinal surgery, ketamine may reduce cumulative 24-h opioid consumption. Ketamine may increase the occurrence of serious adverse events, but the evidence was very uncertain.