Both substance use and obesity are prevalent among youth. As youth age, substance use rates increase and over the past three decades, obesity rates among youth have tripled. While these two factors have both short- and long-term health impacts, little research has explored how substance use and obesity among youth may be related. This study explores the bi-directional longitudinal relationships between substance use and body composition. Participants (N = 704; 50.7% female) were mostly white (86.4%) with a baseline mean age of 14.7 years. Objectively measured body composition was used to calculate body mass index z-scores (BMI z-score) and percent body fat. Cross-lagged structural equation models, accounting for clustering at the school level, were run to determine the longitudinal association between body composition and self-reported substance use (alcohol, cigarette, and marijuana), adjusting for socio-demographic characteristics, pubertal status, and weight satisfaction. Baseline alcohol use predicted decreased BMI z-score at follow-up and a similar association with percent body fat approached significance. Baseline cigarette use predicted increased percent body fat. No longitudinal associations were seen between baseline body composition and future substance use. Our results suggest that substance use contributes to subsequent body composition; however, body composition does not contribute to subsequent substance use. Continued research that explores these relationships longitudinally is greatly needed.