Flexibility is often associated with resilience from adversity. Youth with autism spectrum disorder (ASD) are at risk of stress and trauma yet have inherent difficulties with flexibility, including rigid behaviors, routines, “insistence on sameness,” and lack of social reciprocity. This review highlights literature of physiological and psychological processes related to inflexibility in ASD and proposes a heuristic model to understand mechanisms of resilience in the aftermath of adversity. This article presents the Biosocial Model for Resilience, which posits that interventions that target changes in central, autonomic, and endocrine dysregulation may in turn enhance processes of psychological flexibility (i.e., executive cognitive, emotional, and interpersonal regulation) that increase the likelihood of resilient adjustment in response to stressful experiences. This model of resilience is optimistic in positing that, in addition to critical programs on the prevention of social adversity, future research on flexibility can inform intervention programs that target this specific mechanism to minimize harmful aftereffects in youngsters with ASD.