Mothers of children with Autism Spectrum Disorder (ASD) report more stress, anxiety and depression than fathers and parents of both typically-developing children and children with other disabilities such as Down syndrome. Because women commonly hold the majority of the responsibility for childcare activities and healthcare decisions, maternal depression in a family with a child with ASD involves all members of the family, and research and care should be approached with a family focus. Improving our understanding of the prevalence and relationship of depressive symptoms to family functioning and child outcomes is needed to support professional practices as well as national and state policy decisions. This dissertation is composed of three papers and uses a sequential explanatory mixed methods design to answer three questions: (a) what is the prevalence of depression in this population, (b) what modifiable factors are associated with depression, including self-efficacy and family functioning, and (c) how do mothers with varying levels of depressive symptoms describe their experiences raising a child with ASD? This study also proposes a conceptual model to illustrate factors associated with maternal depression. This is the first study with mothers of children with ASD to explore the role of maternal self-efficacy and family functioning together, and to explore the mother’s perspective using rigorous qualitative methods. A more thorough understanding of depression and the role of associated factors in this population can have implications for the development of more effective screening and targeted interventions.