Theoretically, anxiety sensitivity—fear of anxiety symptoms—enhances perception of and emotional reactivity to autonomic arousal and mental distress, thereby increasing negative affect and motivation to use substances for negative reinforcement. Because no prior study of adolescents has tested if anxiety sensitivity is indirectly associated with substance use problems through symptoms of emotional disorders (i.e., disorders involving high levels of negative affect), the current cross-sectional study examined this theoretical pathway. Participants included ninth-grade students from 10 different high schools in the Los Angeles metropolitan area (N = 3005; 54.3% female). Self-report measures of anxiety sensitivity, emotional disorder symptoms, tobacco dependence, and alcohol and other drug problems were administered. Controlling for sex, race/ethnicity, parental education, school, and impulsiveness, we tested the associations of anxiety sensitivity with tobacco, alcohol, and other drug use problems as well as the indirect effects of anxiety sensitivity on each domain of substance use problems through emotional disorder symptoms. Anxiety sensitivity was associated with more severe tobacco dependence and greater alcohol problems and other drug problems, and anxiety sensitivity further was indirectly associated with all three domains of substance use problems through emotional disorder symptoms. Current findings suggest that adolescents high in anxiety sensitivity tend to experience emotional disorder symptoms, which may increase risk for substance use problems. Interventions that target anxiety sensitivity and enhance negative-affect coping skills may assist in preventing and reducing adolescent substance use problems.