Autism spectrum disorder (ASD) is an increasingly prevalent diagnosis characterized by impairment of social communication and behavioral regulation. Children with ASD seek care more frequently in the emergency department (ED) than their neurotypical peers and the approach to medical evaluation of this population requires heightened attention to a variety of factors. Communication with caregivers, attention to environmental stimulation, identification of accommodation needs, and understanding frequently associated medical conditions are important considerations in ED encounters. Gastrointestinal problems, seizure disorders, and metabolic disease are common causes for ED presentation in children with ASD. A high index of suspicion for underlying medical issues must be maintained, even when children with ASD present primarily for behavioral concerns. Autism spectrum disorder (ASD) is an increasingly prevalent diagnosis characterized by impairment of social communication and behavioral regulation. Children with ASD seek care more frequently in the emergency department (ED) than their neurotypical peers and the approach to medical evaluation of this population requires heightened attention to a variety of factors. Communication with caregivers, attention to environmental stimulation, identification of accommodation needs, and understanding frequently associated medical conditions are important considerations in ED encounters. Gastrointestinal problems, seizure disorders, and metabolic disease are common causes for ED presentation in children with ASD. A high index of suspicion for underlying medical issues must be maintained, even when children with ASD present primarily for behavioral concerns.