Objective: This study examined psychosocial distress and substance use in young adults with asthma (A), obesity (O), comorbid asthma and obesity (AO), or neither (controls). Participants: Eight hundred eighty-one young adults were included in the A, O, AO, or control group. Methods: ANCOVA and logistic regression analyses were performed to compare responses to screeners for psychological distress and substance use among the four groups. Results: Levels of depressive symptoms, worry, nonsuicidal self-injury, emotion dysregulation, and chronic pain symptoms differed across groups, with the A and AO groups showing greater psychological distress than the O and control groups. The AO group exhibited the highest levels of cigarette and smokeless tobacco use, while the O group exhibited the least frequent binge drinking behaviors. Conclusions: Individuals with asthma or comorbid asthma and obesity appear to experience the poorest psychosocial functioning and highest use of tobacco products. Potential mechanisms and implications of these relationships are discussed.