PURPOSE: Postoperative nausea and/or vomiting (PONV/POV) following tonsillectomy occurs in up to 89% of children without antiemetic prophylaxis. Prior systematic reviews have not evaluated the relative efficacy of ondansetron and metoclopramide for PONV/POV, including their adverse effects. METHODS: A systematic search was conducted of five databases from their inceptions to June 19, 2024. Inclusion criteria were randomized controlled trials (RCTs) comparing ondansetron and metoclopramide in pediatric patients undergoing tonsillectomy or adenotonsillectomy. The primary outcome was incidence of PONV/POV. Secondary outcomes were length of hospital stay (LOS) and adverse events including postoperative extrapyramidal reactions and delayed hospital readmissions. Pooled risk ratios (RRs) or mean differences (MDs) and 95% confidence intervals (CIs) were calculated using random-effects meta-analysis. Adjusted RRs were calculated using random-effects meta-regression. Risk of bias and certainty of evidence were assessed using Cochrane RoB 2 and GRADE, respectively. This study was registered in PROSPERO (42,024,499,702). RESULTS: Five RCTs met all inclusion criteria, consisting of 861 patients. Ondansetron significantly reduced risk of PONV/POV by almost 50% (RR 0.48 95% CI 0.31-0.75, moderate quality evidence), compared to metoclopramide. Intraoperative opioid dose did not impact the RR. Ondansetron also significantly shortened LOS (MD - 26.92 min 95% CI - 47.24 min to - 6.60 min, moderate quality evidence). Only two RCTs addressed readmission rates or extrapyramidal reactions, although no events occurred in either study. CONCLUSION: Ondansetron is more effective than metoclopramide for PONV/POV prophylaxis, decreasing the risk of PONV/POV as well as LOS. Continued surveillance for adverse effects may be recommended when using either medication.