African Americans are disproportionately burdened by substance use consequences and criminal justice system involvement, yet their interrelationship over the life course is not well understood. This study aimed to assess how substance use, crime, and justice system involvement may influence one another from adolescence to midlife. Data come from a community cohort of urban African Americans first assessed in childhood and followed up into midlife (nā€‰=ā€‰1242, 606 males, 636 females). We draw on interview data and local, state, and federal criminal records. Participants were assessed at ages 6, 16, 32, and 42, with additional record retrieval at age 52. Utilizing structural equation modeling, we estimate pathways between substance use, criminal behavior, and arrests over time by gender. For males, significant paths were found between childhood behavioral problems and adolescent substance use, delinquency, and police interactions. For females, a significant path was found between childhood behavioral problems and only adolescent delinquency. We observed continuity between substance use and between arrest constructs from adolescence through midlife for men only. Direct paths were found between substance use and later arrests for both males and females. Paths were also observed between arrests and later substance use for both genders. Findings of reciprocal relationships highlight the critical need to break the cycle of substance use and crime and point to specific times in the life course when intervention is necessary. Findings introduce the potential role of the criminal justice system as a key intervention agent in redirecting substance use careers.