Many high-functioning individuals with autism spectrum disorder (ASD) also experience depression and anxiety, yet little is known about mechanisms underlying this comorbidity. Repetitive negative thinking (RNT) about self-referential information is a transdiagnostic cognitive vulnerability factor that may account for the relationship between these two classes of symptoms. We propose a model where negative self-referential processing and cognitive inflexibility interact to increase risk for RNT, leading to internalizing problems in ASD. Examination of interactions within and between two well-characterized large-scale brain networks, the default mode network and the salience network, may provide insights into neurobiological mechanisms underlying RNT in ASD. We summarize previous literature supporting this model, emphasizing moving toward understanding RNT as a factor accounting for the high rates of internalizing problems in ASD. Future research avenues include understanding heterogeneity in clinical presentation and treating cognitive flexibility and RNT to reduce comorbid internalizing problems in ASD.