ABSTRACT Introduction: Existing literature shows that self-concealment increases the risk for substance use while self-compassion protects against substance use, but less is known about possible gender differences that can potentially determine the prediction of substance use by these variables. This study investigated the roles of self-concealment and self-compassion in non-medical substance use, and the differential impact of these variables for male versus female adolescents in Nigeria’s Niger Delta region. The interest is because the communities have hitherto maintained a culture of permissiveness to substance use especially harmful alcohol use. Method: Participants were 564 adolescents (55.7% females), who completed the Self-Concealment Scale, Self-Compassion Scale, and Psychoactive Substance Use Questionnaire. Data were analyzed using Hayes’ regression-based macro for SPSS. Results: Findings indicated that the frequently used substances by the respondents were alcohol (45.9%), tobacco (27.5%), cannabis (18.6%), cocaine (13.5%), and tramadol (12.1%). An increase in self-concealment predicted greater substance use among females but not males. The gender effect was not found for self-compassion as it neither predicted substance use for male nor female adolescents. Conclusion:s By showing that self-concealment increases substance use for female adolescents compared to males, we provide insights into possible targets for psychological intervention programs to ameliorate the use of psychoactive substances among female youths.