BACKGROUND: Ondansetron is an effective antiemetic employed to prevent vomiting in children with gastroenteritis in high-income countries; data from low- and middle-income countries are sparse. METHODS: We conducted a randomized, double-blind, placebo-controlled superiority trial in 2 pediatric emergency departments in Pakistan. Dehydrated children aged 6 to 60 months with ≥1 diarrheal (ie, loose or liquid) stool and ≥1 vomiting episode within the preceding 4 hours were eligible to participate. Participants received a single weight-based dose of oral ondansetron (8–15 kg: 2 mg; >15 kg: 4 mg) or identical placebo. The primary outcome was intravenous administration of ≥20 mL/kg over 4 hours of an isotonic fluid within 72 hours of random assignment. RESULTS: All 918 (100%) randomly assigned children completed follow-up. Intravenous rehydration was administered to 14.7% (68 of 462) and 19.5% (89 of 456) of those administered ondansetron and placebo, respectively (difference: −4.8%; 95% confidence interval [CI], −9.7% to 0.0%). In multivariable logistic regression analysis adjusted for other antiemetic agents, antibiotics, zinc, and the number of vomiting episodes in the preceding 24 hours, children administered ondansetron had lower odds of the primary outcome (odds ratio: 0.70; 95% CI, 0.49 to 1.00). Fewer children in the ondansetron, relative to the placebo group vomited during the observation period (difference: −12.9%; 95% CI, −18.0% to −7.8%). The median number of vomiting episodes (P < .001) was lower in the ondansetron group. CONCLUSIONS: Among children with gastroenteritis-associated vomiting and dehydration, oral ondansetron administration reduced vomiting and intravenous rehydration use. Ondansetron use may be considered to promote oral rehydration therapy success among dehydrated children in low- and middle-income countries.