Pediatric infections account for approximately one-third of all deaths in children under 5 globally. Lactoferrin (LF) supplementation has the potential to reduce infection-related morbidity due to its antimicrobial, anti-inflammatory and immunoregulatory properties. We conducted a systematic review and meta-analysis of oral LF supplementation randomized controlled trials (RCT) in population under 18 years old. The primary outcomes were infection-associated outcomes: late onset sepsis (LOS), diarrhea, and upper respiratory infections (URI). We also analyzed mortality among LOS studies. Of 1,594 citations identified, 25 studies met eligibility criteria, including 10 studies of LOS, 14 of diarrhea and 8 of URI. LF supplementation was associated with fewer patients with culture-proven or probable neonatal LOS compared to placebo (OR: 0.60; 95% CI: 0.42 to 0.86), with fewer patients with diarrhea compared to placebo in children (OR: 0.56; 95% CI: 0.41 to 0.75), and no significant fewer patients with URI (OR: 0.61; 95% CI: 0.27 to 1.40). Before LF can be used as a public health intervention, it is necessary to refine some aspects of the design of future trials. Ideally these trials should be conducted in countries with the highest burden of infections, where the potential benefit is expected to have the largest impact.