Autism spectrum disorder (ASD) is characterized by a preference for predictability or sameness and difficulty coping with unpredictable or unexpected circumstances. Accordingly, individuals with ASD may be more inclined to engage with predictable, non-social stimuli rather than participate in dynamic and unpredictable social interactions. This behavioral pattern may reflect differential mechanisms involved in processing uncertain and certain cues and outcomes in individuals with ASD. Yet, despite the prevalence of such symptoms in ASD and their potential role in core ASD symptomatology, uncertainty processing in ASD is not well understood and the neurobiological mechanisms underlying this atypicality have yet to be studied in this population. Accordingly, the present study aimed to measure neural responses to uncertainty in children with ASD versus typically developing (TD) children using functional magnetic resonance imaging (fMRI), and then to examine how functional brain activation during uncertainty was related to a behavioral measure and self- and parent-reported responses to uncertainty. Results indicated that children with ASD consistently showed attenuated activation of frontolimbic regions during uncertain cues and outcomes across different types of social and non-social stimuli. Behavioral and self- and parent-reported questionnaire measures also indicated atypical responses to uncertainty in the ASD group relative to the TD group. Correlations among neural, behavioral, and questionnaire measures suggested that attenuation of frontolimbic activation during uncertain cues and outcomes was associated with more atypical responses to uncertainty in the ASD group as indexed by the behavioral and questionnaire measures. These results have important implications for understanding core ASD symptomatology, differentiating ASD from other clinical populations, and developing interventions designed to support or ameliorate impaired processing of uncertainty in ASD.