Relative to children without autism spectrum disorder (ASD), children with ASD experience elevated sleep problems that can contribute to behavioral comorbidities. This study explored the interaction between psychophysiology and sleep to determine which children with ASD may be at risk for, or resilient to, effects of poor sleep on daytime behavior. Participants included 48 children (aged 6–10 years) with ASD. Measures of sympathetic nervous system activity (electrodermal activity; EDA) were collected during a baseline and in response to a laboratory challenge task. Parents reported on their children’s sleep problems and behavioral functioning, including broad externalizing symptoms and situational noncompliance, using standardized questionnaires and a clinical interview. EDA moderated the significant positive associations between sleep problems and both behavioral outcomes. The link between sleep problems and broad externalizing symptoms and situational noncompliance was positive and significant in the context of lower baseline EDA and nonsignificant in the context of higher baseline EDA. Sleep problems also interacted with EDA reactivity in predicting situational noncompliance, but not broad externalizing symptoms. Findings highlight the complex interplay among sleep, daytime behavior, and psychophysiology in children with ASD. Results are interpreted in the context of differential susceptibility and dual-risk frameworks. This study underscores the importance of high-quality sleep for children with ASD, especially those with the biological sensitivity or vulnerability factors (i.e., EDA) identified in this study. Clinical implications are discussed, and directions for future research are provided.