Substantial research has linked childhood maltreatment to the development of substance use in adolescence. However, gender differences in the mechanisms that connect child abuse and neglect to substance use remain unclear. In this study, we applied multiple‐group structural equation modeling in a sample of 1,161 youths (boys, n = 552; girls, n = 609) from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) to examine gender differences in the associations between childhood abuse and neglect exposure from ages 0–12 years and substance use severity at age 18 as mediated by early substance use at age 14 and psychological symptoms (anger, anxiety, and depression) at age 16. In both genders, neglect directly predicted substance use severity, β = .25, p < .001 for boys and β = .17, p = .007 for girls; and early substance use, β = .03, p = .002 for boys and β = .06, p = .005 for girls; and anger mediated this association, β = .10, p < .001 for boys and β = .06, p = .005 for girls. Anger mediated paths from abuse in boys, β = .06, p = .018. In girls, early substance use mediated the path from abuse to substance use severity, β = .06, p = .008, with the mediated effect and direct path from abuse to early substance use significantly moderated by gender. For substance use severity, R² = .26 for girls and R² = .27 for boys. These findings demonstrate the prominence of neglect in predicting substance use severity and gender differences in paths from abuse.