BACKGROUND AND OBJECTIVES: Information on the use of prescription medications among children and adolescents in the United States is lacking. We estimate the prevalence of prescription medication use, concurrent use, and potential major drug–drug interactions (DDIs) in this population. METHODS: We conducted descriptive analyses using nationally representative data for people ≤19 years old from NHANES. Data were derived from a medication log administered by direct observation during in-home interviews. Acute medications were used for ≤30 days. Concurrent use was defined as use of ≥2 prescription medications. Micromedex was used to identify potentially major DDIs. RESULTS: During 2013–2014, 19.8% of children and adolescents used at least 1 prescription medication, and 7.1% used acute medications. Concurrent use of prescription medications was 7.5% overall and was highest among boys 6 to 12 years old (12%) and among boys and girls ages 13 to 19 years old (10% for both). Using pooled 2009–2014 data, we found that 8.2% of concurrent users of prescription medications were at risk for a potentially major DDI. The vast majority of interacting regimens involved antidepressants and were more common among adolescent girls than boys (18.1% vs 6.6%; P < .05), driven largely by greater rates of use of acute medications. CONCLUSIONS: Many US children and adolescents use prescription medications with nearly 1 in 12 concurrent users of prescription medications potentially at risk for a major DDI. Efforts to prevent adverse drug events in children and adolescents should consider the role of interacting drug combinations, especially among adolescent girls.