Background: Previous research supports a possible protective effect for physical activity against adolescent smoking. However, it is not clear whether the effect of physical activity on smoking is direct (e.g., time spent in physical activity) or indirect through another variable. One such variable is global physical self-concept (GPSC). Briefly, GPSC is a general perception of one's physical self, including appearance and physical activity competence. Purpose: This study tested a structural equation model of the relationship between physical activity and smoking, with direct effects from physical activity to smoking and an indirect effect through GPSC. Methods: Participants were 983 12th graders taking part in a study of the biobehavioral predictors of adolescent smoking adoption. Results: Controlling for covariates of adolescent smoking (e.g., peer smoking, alcohol use) and GPSC (e.g., body mass index, perceived physical appearance), physical activity had an indirect effect on smoking through its effects on GPSC, suggesting that the potential beneficial effects of physical activity on adolescent smoking may depend, in part, on GPSC. Conclusions: These results suggest that an adolescent's perception of the physical self may be one important factor to consider in youth smoking interventions. Further research is necessary to evaluate the longitudinal relationship between physical activity, GPSC, and smoking.