Highlights:

• Societal gender inequality relates to gender differences in adolescent substance use.
• The gender gap in adolescent substance use is larger in countries with higher levels of gender inequality.
• Girls in these countries were less likely to get drunk, use alcohol or smoke cigarettes than boys.

In summary, our study highlights that structural gender inequality is associated with gender differences in adolescent involvement in substance use. Considering the current large variations in the direction and magnitude of gender differences in adolescent substance use showed by our findings, when orienting the transition towards a more gender-equal society it is important to implement prevention programs focused on specific health behaviours and contexts. International health institutions and national health systems should adapt prevention policies to the specificity of local contexts, by using empirical evidence to inform programs and evaluating their effectiveness on the target outcomes