A growing body of literature suggests that youth with severe obesity are engaging in substance use. The purpose of the present study was to examine profiles of substance use among adolescents with severe obesity and examine how these profiles are associated with depressive symptomology using data from the Youth Risk Behavior Surveillance System. The sample included 597 girls and 626 boys who self-reported height and weight and alcohol, tobacco, marijuana, and illicit substance use. Latent profile analysis revealed four distinct groups ranging from non-users to polysubstance users with non-users reporting the highest depressive symptoms. These results suggest those with severe obesity might be using substances to self-medicate to treat poor mental health; however, longitudinal research is necessary to examine pathways to substance use among severely obese youth.