Objective The aim of this study was to examine the associations between age and ethnicity on the development of substance use behaviors among Hispanic and non‐Hispanic White (NHW) adolescent and young adult (AYA) childhood cancer survivors. Methods Participants were recruited from a single institution through the CHOC Children's Hospital Cancer Registry and included 55 Hispanic and 61 NHW AYA childhood cancer survivors, ages 12 to 33 years (Mean age ± SD: 19 ± 4.2). Smoking, alcohol, and drug use were measured using the Child Health Illness Profile – Adolescent Edition. Results Hispanic AYA survivors were less likely to be medically insured and reported lower household income than their NHW counterparts (P < 0.001 and P < 0.001, respectively). After controlling for socioeconomic differences and gender, age and ethnicity were significant predictors of substance use among AYA survivors. Hispanic survivors reported less lifetime use of cigarette smoking compared with NHW survivors (OR 0.17, 95% CI, 0.03‐0.80). Older age, for both Hispanic and NHW survivors, was found to be a risk factor for lifetime substance use and current alcohol/hard liquor consumption and binge drinking (P < 0.05). Conclusions Young adult childhood cancer survivors and NHW survivors are at greatest risk for developing substance use behaviors. The frequency of substance use among AYA survivors appears to increase as they transition into adulthood. These findings emphasize the need to improve long‐term health behavior screening and develop effective interventions on reducing substance use behaviors in this vulnerable population.