School-based extracurricular activity involvement has been associated with lower levels of substance use among adolescents from various populations; however, these associations have only been slightly examined among American Indian (AI) adolescents. Building from various theoretical perspectives, it was hypothesized that AI adolescents' perceived access to and the intensity (i.e., frequency) of participation in extracurricular activities would be associated with lower substance use and less engagement in risky substance use behaviors (i.e., being drunk or high at school, riding/driving with an intoxicated driver, and selling drugs). The moderating influences of sex, age, reservation residence, and metropolitan status also were examined. Data from the 2010 Arizona Youth Survey were analyzed for 5,701 8th, 10th, and 12th grade AI adolescents (49.1% female). The expected protective effects of extracurricular participation were demonstrated, such that high levels of perceived availability and intensity of participation consistently predicted low levels of all outcomes. Some of these associations were moderated by one or more demographic factors, with unique patterns emerging for each behavior. Ultimately, the findings suggest that AI adolescents benefit from the availability of extracurricular activities and intensity of participation in them, but the degree of the effect is contingent upon other individual and contextual characteristics.