Autistic adults experience a higher rate of physical and mental health conditions and lower rates of employment and post-secondary education participation than their non-autistic counterparts, which may affect negatively quality of life. Limited information exists on predictors of quality of life for autistic individuals, or how quality of life compares to non-autistic individuals. Our aims were to (a) examine and compare indicators of physical (e.g. sleep quality) and mental health (e.g. anxiety) on quality of life among a sample of 244 autistic and 165 non-autistic individuals aged 15–80 years and (b) examine factors contributing to quality of life 2 years later among the autistic sample ( n = 93). Participants were from two Australian longitudinal studies. The pattern of results for quality of life was similar across the autistic and non-autistic groups, with depression symptomatology, psychological well-being, sleep quality and autonomic symptoms all significantly predicting quality of life. In addition, among the autistic group, baseline quality of life had the greatest influence on quality of life 2 years later. These findings have implications for support services for autistic individuals, implying that in order to improve quality of life, mental health, particularly depression, needs addressing. Given known relationships between sleep and mental health, an intervention addressing these may have greatest clinical impact on quality of life among autistic individuals. Lay Abstract Research shows that autistic adults are at risk of a range of physical (e.g. sleep difficulties) and mental health (e.g. anxiety) conditions, as well as lower employment and post-secondary education participation; these all can affect one’s quality of life. However, we have little information about what affects quality of life for autistic individuals across the lifespan and whether this differs from non-autistic people. We determined what factors (e.g. mental or physical health challenges) affected quality of life in a large group of autistic individuals aged 15–80 years compared with similar age non-autistic individuals. We also examined what factors affected quality of life of the autistic group 2 years later. We found a similar pattern of results for the autistic and non-autistic groups; depression symptoms, psychological well-being, sleep quality and autonomic symptoms (e.g. sweating) were all significant predictors of quality of life. In addition, among the autistic group, baseline quality of life had the most influence on quality of life 2 years later. These results have implications for support services, as they highlight the relationship between mental health (especially depression) and quality of life. Given that sleep challenges (e.g. insomnia) are related to mental health, an intervention addressing both insomnia and mental health may be most useful in helping autistic individuals improve their quality of life.