Parental mental health-related quality of life affects the ability of a family to cope with and adapt to the presence of a disability in a family member, such as their child. Therefore, understanding variables that influence parental mental health-related quality of life in families of children with autism spectrum disorder is important. The purpose of this study was to examine the pathways to parental mental health-related quality of life, focusing on the variables of parental stress, children’s performance, medical support, and neighbor support. These variables were hypothesized to be interrelated with one another and directly or indirectly associated with parental mental health-related quality of life. Samples of this study were 429 parents of children with autism spectrum disorder aged 6–17 years in the United States. These parents were selected from the respondents interviewed over the telephone by the 2007 National Survey of Children’s Health. The item indicators selected from the survey were used to construct latent variables for the investigated variables. Structural equation modeling was used to analyze the data. Results showed that parental stress, children’s performance, medical support, and neighbor support played important roles in the pathways. Implications and limitations are discussed.