This review aimed to meta-analyze evidence of efficacy and safety of one single dose of ondansetron for vomiting in children and adolescents with acute gastroenteritis. Database searches of MEDLINE (PubMed), Scopus (Elsevier), Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov up to November 2019 were performed. Only randomized clinical trials versus placebo were considered. Fixed and random effect models were used for the analyses of pooled data. Thirteen randomized clinical trials (2146 patients) were finally included. One single dose of ondansetron showed to produce (1) higher chance of vomiting cessation within 8 h (RR 1.41, 95% CI 1.19-1.68; low-quality evidence); (2) lower chances of oral rehydration therapy failure (RR 0.43, 95% CI 0.34-0.55; high-quality evidence), intravenous hydration needs (RR 0.44, 95% CI 0.34-0.57; high-quality evidence), and hospitalization rates within 8 h (RR 0.49, 95% CI 0.32-0.75; high-quality evidence); and (3) no statistically significant differences in return visits to emergency department (RR 1.14, 95% CI 0.74-1.76; high-quality evidence) compared with placebo. Further studies are necessary to better assess long term efficacy and safety of ondansetron in this context.Conclusions: Mixed evidence was found via few studies about the efficacy and safety of a single dose of ondansetron in the pediatric population.What is known:• Ondansetron use for vomiting in pediatric acute gastroenteritis is increasing worldwide.• Actual convictions come from studies evaluating one and more than one dose of the drug.What is new:• This is the first review to collect data about the effects of one single dose of ondansetron on strong and temporally homogeneous clinical outcomes.• This study supports the use of one dose of ondansetron in pediatric acute gastroenteritis.• Further studies are necessary to assess its long-term efficacy and safety.