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Substance use (SU) problems are critical public health concerns. This study investigated how childhood risk factors and cannabis age of onset (CAO) in adolescence predict later SU problems, using data from the two cohorts of the Quebec Longitudinal Study of Child Development (N = 306; 57% female; N = 1489; 54% female), followed from birth to age 23. A direct association between early CAO and increased cannabis use problems was found in males (cohort 1: β = -0.47; cohort 2: β = -0.22), but not in females. In both sexes, CAO was indirectly associated with later cannabis use problems via increased adolescent cannabis use frequency (cohort 1: ab = -0.41; cohort 2: ab = -0.35). Similar indirect associations were observed between CAO and other SU problems (including tobacco and alcohol), via adolescent cannabis use frequency (cohort 1: ab = -2.63). Parental cannabis use, adverse childhood experiences, and childhood externalizing behaviors (i.e., physical aggression and ADHD symptoms) were associated with early CAO and subsequent CU problems. These findings support developmental models linking early risk exposures to maladaptive substance use pathways and underscore the importance of prevention strategies targeting early cannabis initiation and modifiable early-life risk factors to reduce long-term SU-related problems.