Summary Spirituality is an ancient concept with many contemporary applications to the field of health promotion. While recognized in the UN Convention on the Rights of the Child as a basic human right, definitional misunderstandings about what spirituality is, and is not, and the mechanisms by which it affects the health of young people, remain. In this cross-national analysis involving >75 000 adolescents from 12 countries, we examined the relative importance of each of four spiritual health domains (connections to self, others, nature and the transcendent) in the lives of young people, and how these connections relate to a standard indicator of positive mental health status. Descriptive and applied regression analyses confirmed two major findings: (i) boys and girls in all 12 countries ranked the importance of each of the four domains in the same order, with ‘connections to self’ identified as most important; and (ii) both direct and indirect pathways are evident that connect the remaining three domains to positive mental health status, but through strong connections to self. Based on our scale items, fostering a strong connection to self, which involves cultivating a sense of meaning, purpose and joy in the lives of adolescents, appears most fundamental to fostering optimal mental health. This may be achieved directly or, dependent upon context and culture, indirectly with emphasis on the connections afforded by the other three domains. Such findings provide important insights to guide the content of adolescent health promotion interventions.