Individuals with autism spectrum disorder (ASD) are at an increased risk of mental health problems, with depression being one of the most common presenting issues. The current study used a diathesis-stress model to investigate stressors (parent distress and negative life events [NLE]) and vulnerabilities (youth age and intellectual functioning) as predictors of depressive symptoms in youth with ASD. Parents of youth with ASD (N = 91; ages 7 to 25 years) completed online questionnaires about demographic variables, distress, NLE, and youth depression. High parent distress and exposure to 3 or more NLE were associated with symptoms of depression in individuals with ASD. Also, youth with ASD who were younger, or who were noted to have average or above-average intellectual functioning, were reported to have higher depression levels than other individuals with ASD. None of the vulnerabilities were found to moderate the relationships between stressors and depression.