North American Indigenous (i.e., American Indian and Canadian First Nations) youth experience inequities in rates of substance abuse and dependence. Despite this, few longitudinal studies examine the developmental course of substance use disorders (SUD) among community-based samples of Indigenous youth. The purpose of the study was to examine onset and predictors of nicotine dependence, alcohol use disorders, marijuana use disorders, any SUD, and multiple SUDs across the entire span of adolescence among a longitudinal sample (N = 744) of reservation/ reserve Indigenous youth in the upper-Midwest of the United States and Ontario, Canada. Using discrete time survival analysis, the results show that rates of meeting criteria for substance use disorders by late adolescence were 22% for nicotine, 43% for alcohol, and 35% for marijuana. Peak periods of risk for new nicotine dependence and marijuana use disorder cases occurred around 14 years of age, whereas peak periods of risk for new alcohol use disorder cases emerged slightly later around 16 years of age. We found high rates of SUD comorbidity, and the cumulative probability of developing two or more SUDs during adolescence was 31%. Internalizing disorders increased the odds of nicotine dependence and multiple substance use disorders, while externalizing disorders increased the odds of all outcomes except nicotine dependence. Gender, age, and per capita family income were inconsistently associated with SUD onset. The findings are embedded within broader substance use patterns identified among Indigenous youth, and prevention, intervention, and treatment implications are discussed.