Parents of autistic children show more problems of stress and well-being than parents of neurotypical children. However, not all parents show these problems. The differences can be due to environmental antecedents, personal antecedents, or mediating processes. The aim of this study was to explain how these factors can predict stress and well-being in parents of autistic children. The study consisted of 37 parents of children with autism and 41 parents of neurotypical children. Our results showed that parents of autistic children have a lower well-being and higher stress. This is due to the parents’ perception of their children’s difficulties, their use of reappraisal, and, in part, due to their children’s autism diagnosis. Future interventions should aim to target those factors.