Background While typologies of substance use disorder are very informative, they are still scarcer. The aim of this study was to consider a classification system of substance use among adolescents based on types of substance used and levels of use, and to compare identified groups on sociodemographic characteristics, mental and physical health factors, and other psychological indices. Methods A total of 23,294 17-year-old French adolescents were assessed on mental health factors (depression, suicide, visits to a mental health professional), physical health factors (health self-perception, body shape perception, body mass index), family relationships, perceptions of substance use risk, and vision of the future. Results Hierarchical Cluster Analysis identified four classes of adolescents: ‘Adolescents who use Occasionally/experimentally Tobacco and Alcohol’ (n = 7328, 35.3%), ‘Adolescents who do not use drugs’ (n = 5218, 25.1%), ‘Adolescents who use Tobacco, Alcohol, Cannabis’ (n = 6804, 32.8%), and ‘Adolescents who use Multi-drugs’ (n = 1403, 6.8%). The two first were mostly high school girls, with no mental and physical health issue, accurate perception of substances uses risk, and positive vision of their future. They differed regarding parental socioeconomic status and body mass index. The two latest were mostly boys, with poor school performance, bad family relationships, mental health issues, incorrect perception of substances uses risk, and negative vision of their future. They differed regarding parental socioeconomic status, weight and weight perception. Conclusions Our results confirm the heterogeneous nature of drug use in adolescents, the relevance of typologies, and their importance for future public health policy.