The aim of this study was to compare parental stress and resilience in parents of children with autism spectrum disorder (ASD), Down syndrome (DS), and typical development (TD), and analyze the relationship between these two constructs. A total of 97 parents participated (ASD: n = 32, DS: n = 23, and TD: n = 42). The instruments used were the Parental Stress Index and the Resilience Scale. The ASD group obtained higher parental stress related to the child’s characteristics but not related to the parents’ characteristics. The three groups obtained moderate resilience, and high resilience was associated with low parental stress in the ASD and DS groups. The higher parental stress obtained in the ASD group, compared to the DS group, was not associated with aspects related to the parents or demographic and social factors of the families but rather with aspects related to the child and the characteristics of each disorder, as perceived by the parents.