Quality of life (QoL) has been extensively studied within the field of intellectual disability, with various theoretical frameworks being developed to guide the provision of appropriate supports in daily life. However, the role that self-determination can play in the QoL of adolescents with intellectual disability has received little attention. This study explores the impact of personal characteristics (age, gender, intellectual disability level, and diagnosis of autism spectrum disorder) and the context-related variable of self-determination on QoL, overall and at domain level, in 100 adolescents with intellectual disability in a single school. The KidsLife scale of QoL and the AUTODDIS scale of self-determination were applied, with the participants' teachers acting as respondents. The variable of self-determination had the highest influence on QoL, being positively related to all the domains under investigation. A diagnosis of autism spectrum disorder was positively related with Personal Development, Material Well-being, and Social Inclusion domains. Intellectual disability severity only had a negative relationship with QoL total level when not considered simultaneously with self-determination. We discuss the role that self-determination plays in the quality of life of youth with intellectual disability.