This study examines the relationships between six spirituality-related attributes and quality of life (QOL) in adolescents, and the extent to which these relationships are mediated by perceived physical and mental health status and five important life domains (family, friends, living environment, school experiences, and perception of self). The data were obtained via a cross-sectional health survey of 8,225 adolescents in British Columbia, Canada. Structural equation modeling was used to test the hypothesized relationships. All spiritual attributes are significantly associated with three or more of the life domains, and four of the attributes significantly explain global QOL after controlling for the other variables in the multivariate model. The attributes indicative of adolescents' feelings about their future and other existential matters were found to be relatively most explanatory with respect to global QOL. The predominant mediators include adolescents' satisfaction with their family, their perceived self, and their perceived mental health status. Spirituality is important with respect to adolescents' QOL. The multivariate model provides preliminary insights into the relevance of several attributes of spirituality and the possible mechanisms by which these attributes may contribute to adolescents' QOL.