(1) Background: here is a growing need for integrated and multidimensional approaches to health, especially in a particular category of populations, school-dropout (SD) adolescents, who are traditionally more prone to risky behavior. This study aimed to describe the association between possible risk factors (substance use, eating disorders, social addiction) and well-being perception through the application of a personalized well-being index (PWBI) in SD youths. (2) Methods: Data were collected in 450 school-dropout adolescents (19 ± 2 years, male 308); the health-related quality of life (HRQoL) and risk behaviors were assessed by means of a battery of standardized questions. (3) Results: The results revealed an altered perception of well-being in association with eating disorders ( < 0.001), the use of psychotropic drugs ( < 0.001), and the amount of their consumption ( < 0.05). In particular, there was a decrease in emotional state ( < 0.001) and PWBI ( < 0.001) in the presence of eating disorders, and an impairment in all PWBI components, emotional states ( < 0.001), lifestyle habits ( < 0.05), and social contexts ( < 0.001) when taking psychotropic drugs. (4) Conclusions: risk or unhealthy behaviors significantly worsen individual well-being. This study highlights the change of paradigm from a disease-oriented model to an educationally strength-based model when monitoring psychosocial well-being in order to define preventive and health promotion strategies in a vulnerable category of the population.