Prenatal cocaine exposure (PCE) has been associated with child and adolescent externalizing behaviors and early substance use, yet few studies investigated its association with substance use disorder (SUD) in emerging adults. The present study examined the association of PCE with SUD in emerging adulthood, and whether childhood externalizing behaviors and adolescent substance use mediated the relationship. Participants were 367 (187 PCE; 53% female) adults at age 21, primarily urban African American who were recruited at birth. PCE and exposure to alcohol, tobacco, and marijuana were determined using biologic assays for drug metabolites and/or maternal self-report at birth. Offspring externalizing problems were assessed using the Youth Self-Report at age 12, substance use and substance use-related problems via biologic assays and/or self-report at age 15, and SUD determined using DSM-5 diagnostic criteria at age 21. About 32.3% of the emerging adults were determined to have marijuana use disorder, 30.3% tobacco use disorder, and 15.5% alcohol use disorder. PCE was related to greater externalizing behaviors at age 12 (β = 0.12, p = .042), which in turn was related to SUD (β = 0.22, p = .008). PCE was also related to substance use, mainly marijuana, at age 15 (β = 0.22, p = .011), which was related to SUD (β = 0.51, p < .001). Total indirect effects including these two pathways were significant (β = 0.19, p = .002). PCE may increase risk for SUD in emerging adulthood through childhood externalizing behaviors and adolescent substance use. ●Prenatal cocaine exposure (PCE) increased risk for SUD in emerging adulthood.●PCE was indirectly related to SUD at age 21 via adolescent substance use.●This study provides critical implication for reducing intergenerational continuity of SUD.