Background and Objective: Gambling is an increasing concern among adolescence, yet there has been limited investigation into school-level factors that may increase the risk for gambling. The current study examined the relationship between substance use and gambling, and explored the influence of school context on adolescent gambling. Methods: Data come from 25,456 students in 58 high schools participating in the Maryland Safe and Supportive Schools Initiative. Youth-reports of socio-demographics, lifetime gambling, and past-month substance use (ie, alcohol, cigarette, marijuana, non-medical prescription drug) were collected. School-level characteristics were student suspension rate, student mobility, percentage of students receiving free/reduce-priced meals, percentage of African American students, urbanicity, gambling prevalence, gambling problem prevalence, and substance use prevalence. Weighted multilevel analyses were conducted. Results: One-third (n = 8,318) reported lifetime gambling, and 10% (n = 2,580) of the full sample, or 31% of the gamblers, experienced gambling problems. Being male and alcohol, marijuana, and non-medical prescription drug use were associated with twice the odds of gambling. Among gamblers, being male, African American, and cigarette, marijuana, and non-medical prescription drug use were associated with higher odds of gambling problems. The school-level factors of suspension rate and percentage of African American had minimal, inverse associations with gambling; however, none were related to gambling problems. Conclusions: Multilevel results indicated that adolescents that are male and use substances are more likely to gamble and have gambling problems. Scientific Significance: The findings indicate a need for prevention programs targeting risky behaviors to also target gambling as such behaviors often co-occur among adolescents.