Migraine is one of the most common neurologic disorders in children and adolescents. However, a quantitative comparison of multiple preventive pharmacologic treatments in the pediatric population is lacking. To examine whether prophylactic pharmacologic treatments are more effective than placebo and whether there are differences between drugs regarding efficacy, safety, and acceptability. Systematic review and network meta-analysis of studies in MEDLINE, Cochrane, Embase, and PsycINFO published through July 2, 2018. Randomized clinical trials of prophylactic pharmacologic treatments in children and adolescents diagnosed as having episodic migraine were included. Abstract, title, and full-text screening were conducted independently by 4 reviewers. Data extraction was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis network meta-analysis guidelines. Quality was assessed with the Cochrane Risk of Bias tool. Effect sizes, calculated as standardized mean differences for primary outcomes and risk ratios for discontinuation rates, were assessed in a random-effects model. Primary outcomes were efficacy (ie, migraine frequency, number of migraine days, number of headache days, headache frequency, or headache index), safety (ie, treatment discontinuation owing to adverse events), and acceptability (ie, treatment discontinuation for any reason). Twenty-three studies (2217 patients) were eligible for inclusion. Prophylactic pharmacologic treatments included antiepileptics, antidepressants, calcium channel blockers, antihypertensive agents, and food supplements. In the short term (<5 months), propranolol (standard mean difference, 0.60; 95% CI, 0.03-1.17) and topiramate (standard mean difference, 0.59; 95% CI, 0.03-1.15) were significantly more effective than placebo. However, the 95% prediction intervals for these medications contained the null effect. No significant long-term effects for migraine prophylaxis relative to placebo were found for any intervention. Prophylactic pharmacologic treatments have little evidence supporting efficacy in pediatric migraine. Future research could (1) identify factors associated with individual responses to pharmacologic prophylaxis, (2) analyze fluctuations of migraine attack frequency over time and determine the most clinically relevant length of probable prophylactic treatment, and (3) identify nonpharmacologic targets for migraine prophylaxis.