Objective: The present study aimed to characterize the association of perceived gender discrimination and illicit drug use among a sample of African American (AA) and European American (EA) adolescent girls and young women. Method: Data were drawn from a high-risk family study of alcohol use disorder of mothers and their offspring (N = 735). Multinomial regressions were used to examine whether experience of offspring and maternal gender discrimination were associated with offspring illicit drug use (cannabis, cocaine, ecstasy, PCP, opiates, hallucinogens, solvents, sedatives, or inhalants). Outcomes included offspring age of drug use initiation (age ≤ 14) and lifetime heavy drug use (≥ 50 times) of 1 or more illicit substances. Interactions between race and offspring gender discrimination were modeled to assess for race differences. Results: Results revealed that gender discrimination was associated with a greater likelihood of offspring early initiation (relative risk ratio [RRR] = 2.57, 95% CI [1.31, 5.03]) versus later initiation (RRR = 1.33, 95% CI [0.80, 2.24]). Offspring gender discrimination was associated with offspring heavy drug use (RRR = 2.09, 95% CI [1.07, 4.06]) and not associated with moderate/light use (RRR = 1.44, 95% CI [0.86, 2.42]), but post hoc tests revealed no significant group differences. Conclusions: Findings suggest that perceived offspring gender discrimination is associated with early drug use initiation. Gender discrimination, particularly at an early age, has a potential to cause harm, including drug use. Implementation of policies that foster environments that eliminate gender bias and discrimination at an early age should be prioritized. Gender-responsive treatment merits consideration by substance use treatment providers. Public Significance Statement: This study indicates that adolescent females who experience gender discrimination, are more likely to initiate drugs at an earlier age. Targeting gender discrimination during adolescence may be important, before gender norms become rooted into one’s trajectory.