© 2015 Taylor & Francis Group, LLC. Background: School-level characteristics are related to students substance use, but little research systematically examined multiple school characteristics in relation to different types of substance use across grade levels. Objectives: This study examines multiple school-level characteristics as correlates of students tobacco, alcohol, marijuana, and combined substance use across three grade levels. Methods: Students (N = 23,615) from 42 urban and suburban middle schools and 24 high schools in the U.S. reported on their tobacco, alcohol, and marijuana use. Students mean age was 14 years; 47% were male, 53% African American, and 41% Caucasian. School-level data included poverty, racial composition, academic achievement, student-teacher ratio, absenteeism, and school size. Multilevel logistic and Poisson regressions tested associations between school-level predictors and adolescent substance use in middle school, early high school, and late high school. Results: School-level poverty, more ethnic minority students, low achievement, and higher absenteeism were related to alcohol, marijuana, and combined substance use, particularly at lower grade levels. By contrast, cigarette smoking was more prevalent in more affluent high schools with more White students. After adjusting for other school characteristics, absenteeism emerged as the most consistent predictor of student substance use. Conclusions/Importance: Interventions addressing absenteeism and truancy in middle and high schools may help prevent student substance use. Schools serving poor, urban, and mostly minority students may benefit from interventions targeting alcohol and marijuana use, whereas interventions focusing on tobacco use prevention may be more relevant for schools serving more affluent and predominantly White students.