The purpose of this study was to gain new understanding of autonomic nervous system (ANS) dysfunction in familiar and unfamiliar social situations in children with autism spectrum disorder (ASD). Both Children with ASD and typically developing peers viewed three sets of stimuli on a computer screen: 1) a screensaver (initial and final baseline), 2) objects moving to music (attention), and 3) narratives produced by both a caregiver and a stranger (familiar and unfamiliar social situations). Physiological measures of heart rate and skin conductance were acquired to assess ANS functioning. It was expected that 1) ANS activity would differ between children with ASD and typically developing peers at baseline, 2) differences in ANS activity between the two groups would be greater in the attention vs. the baseline task, and 3) differences in ANS activity between the two groups would be greater in the unfamiliar vs. the familiar tasks. Results showed that sympathetic, but not parasympathetic, arousal was greater for children with ASD as compared to typically developing children, but these measures did not differ across tasks. Results are interpreted to suggest that children with ASD perceived the experimental conditions as more challenging as compared to children who are typically developing.