Prebiotics, defined as nondigestible dietary ingredients resistant to gastric acidity and fermented by the intestinal flora, are used to positively influence the composition of intestinal flora, thereby promoting health benefits. The objective of this systematic review was to assess the efficacy of prebiotics in the prevention of acute infectious diseases in children. A systematic literature search was conducted using the Ovid Medline, Scopus, Web of Science, and Cochrane Library's Central databases. Finally, five randomized controlled trials, all of them investigating infants and children 0–24 months of age, were included in the review. Pooled estimates from three studies revealed a statistically significant decrease in the number of infectious episodes requiring antibiotic therapy in the prebiotic group as compared with the placebo group (rate ratio 0.68; 95% confidence interval 0.61–0.77). Studies available indicate that prebiotics may also be effective in decreasing the rate of overall infections in infants and children 0–24 months of age. Further studies in the age group 3–18 years are required to determine whether prebiotics can be considered for the prevention of acute infectious diseases in the older pediatric population.