Background: Studies show that food insecurity is associated with adverse health behaviors for children and adults. However, published data among adolescents are limited. The objective of this study was to examine the association between food insecurity and substance use behaviors among US high school students. Methods: Data from the 2017 Youth Risk Behavior Survey in 10 states were combined to examine the association between household food insecurity and adolescent use of alcohol, marijuana, prescription opioid misuse, and illicit drugs using logistic regression. Results: Among surveyed respondents, 12.3% of high school students reported experiencing food insecurity. In unadjusted analyses, the prevalence of substance use was higher among students with food insecurity compared to food secure students: current binge drinking (16.2% vs 11.5%), current marijuana use (24.0% vs 16.2%), lifetime prescription opioid misuse (21.3% vs 12.6%), and lifetime use of illicit drugs (12.3% vs 5.0%) (all p < 0.05). In adjusted models, food insecurity was associated with lifetime prescription opioid misuse and lifetime use of illicit drugs (aPR 1.38 and 1.70, respectively). Conclusion: Students with food insecurity are a potential group at a higher rise of substance misuse and may benefit from prevention programs designed to address their needs.