The present study investigated whether adolescent cigarette, alcohol, marijuana, and hard drug use predicts life satisfaction in young adulthood. Survey data were used from a longitudinal cohort of 2376 adolescents at ages 18 and 29, originally recruited from California and Oregon middle schools at age 13. Results of multivariate models indicated that use of cigarettes and hard drugs at age 18 was associated with lower life satisfaction at age 29, controlling for adolescent environmental, social, and behavioral factors related to lower life satisfaction, including poor mental health, loneliness, poor social skills, and Black race. Adolescent alcohol and marijuana use were not significantly related to adult life satisfaction. Low income, poor health, and cigarette use during adulthood each independently mediated the relationship between adolescent cigarette use and adult life satisfaction, together explaining 84.58% of the effect. Adult hard drug use mediated the effect of adolescent hard drug use, explaining 54.79% of the effect. Results suggest that some forms of adolescent substance use limit socio-economic opportunities, and have a lasting effect on health, consequently decreasing life-satisfaction. Continued use of substances may also lead to lower subjective well-being over time. Findings indicate a need for programs that increase social skills and effectively prevent adolescents from using substances, perhaps by incorporating information about consequences of use for socio-economic status, health, and well-being over the long term.