North American Indigenous communities experience disproportionately high rates of substance use, abuse, and dependence and their accompanying consequences. This study uses group‐based trajectory modeling of past‐year substance use (alcohol, marijuana, and cigarettes) with a longitudinal sample of Indigenous adolescents from the northern Midwest and Canada (spanning ages 10–18 years). The early‐onset trajectory (36.3%) had more adverse psychosocial difficulties at baseline than the mid‐onset group (38.3%); both trajectories were associated with several negative outcomes at the end of the study. The late‐onset trajectory (25.3%) did not initiate substance use until later adolescence and had far better outcomes at the last wave of the study. Timing of onset matters. Prevention efforts should begin in late childhood and continue through mid‐adolescence.