Employing a cohort sequential design and multilevel modeling, the effects of child and family stressors and maternal depressed mood on the self-rated health of 110 mothers of children with autism spectrum disorder were assessed over a 12-year period when children in the study were 7-19 years old. Findings indicate a significant decline in self-rated health over time. In addition, child and family stressors, as well as maternal depressed mood, exerted significant between-persons effects on self-rated health such that mothers who reported more stressors and depressed mood across the study period were less likely to rate themselves in better health across that period. In addition, a significant within-person relationship between maternal depressed mood and self-rated health was found, indicating that at times when mothers reported higher levels of depressed mood than usual (their personal average across the study), they were significantly less likely to report better self-rated health. Finally, maternal depressed mood partially mediated the between-persons effects of child and family stressors on self-rated health such that increased stressors led to increased maternal depressed mood which, in turn, led to poorer maternal self-rated health. Findings suggest that chronic stressors erode maternal health over time and that depression may be an important mechanism linking stressors to decreased maternal health.