Background Few data describing prehospital pediatric substance misuse exist. The objective of this study was to characterize substance misuse in North Carolina pediatric patients receiving emergency medical services (EMS) care. Methods We conducted a retrospective cross-sectional study of patients aged < 16 years transported by EMS for substance misuse. Data were obtained from a statewide repository including patients treated for confirmed or suspected misuse of marijuana, alcohol, benzodiazepines, opioids, stimulants, acetaminophen, antidepressants, or other drugs. Results Of 45,855 EMS encounters, 448 patients misused drugs. Most patients were female (56.7%), White (50.9%), adolescent (73.8%), and resided in Central North Carolina (54.0%). A plurality of cases was rural (46.2%), followed by urban (27.9%) and regional city/suburban counties (25.7%). Calls most often originated in residential locations (68.5%). Drugs identified during EMS calls included alcohol (24.2%), marijuana (24.2%), benzodiazepines (8.8%), antidepressants (8.8%), stimulants (6.8%), opioids (5.9%), and other medications (17.6%). Motivations for drug use were recreational (58.4%), self-harm (24.6%), and accidental (17.0%). Limitations Due to insufficient data documentation, one EMS system was removed from analysis. Additionally, misclassification of type of drug or intention of drug use is possible due to the use of free-text patient narratives. Conclusions EMS responded to a vast variety of drug misuse among pediatric patients including prescription medications, alcohol, marijuana, and illicit drugs. Accidental ingestions occurred exclusively in infant/preschool ages and intent for recreation or self-harm primarily occurred in adolescents. By increasing awareness of the more common pediatric patient characteristics associated with the type and reason for drug use, EMS agencies can improve pediatric readiness among prehospital clinicians.