Optimizing antibiotic therapy is imperative with rising bacterial resistance and high infection mortality. Extended infusion defined as a continuous infusion (COI) or prolonged infusion (PI) of beta-lactams and glycopeptides might improve efficacy and safety compared to their intermittent administration (IA). This study aimed to evaluate the efficacy and safety of extended infusion in pediatric patients. Adhering to Cochrane standards, we conducted a systematic review with meta-analysis investigating the efficacy and safety of COI (24 h/d) and PI (>1 h/dose) compared to IA (≤1 h/dose) of beta-lactams and glycopeptides in pediatrics. Primary outcomes included mortality, clinical success, and microbiological eradication. Five studies could be included for the outcome mortality, investigating meropenem, piperacillin/tazobactam, cefepime, or combinations of these. The pooled relative risk estimate was 0.48 (95% CI 0.26–0.89, p = 0.02). No significant differences between the administration modes were found for the outcomes of clinical success, microbiological eradication (beta-lactams; glycopeptides), and mortality (glycopeptides). No study reported additional safety issues, e.g., adverse drug reactions when using COI/PI vs. IA. Our findings suggest that the administration of beta-lactams by extended infusion leads to a reduction in mortality for pediatric patients.