ObjectiveTo assess the impact of the consumption of licit and illicit substances on the oral health‐related quality of life (OHRQoL) of adolescents from public schools in the south of Brazil.MethodsThis cross‐sectional study was carried out with a random sample of adolescents aged between 17 and 18 years old from Santa Maria, Brazil. The consumption of licit and illicit substances was measured through a self‐administered questionnaire with questions from the National Survey of Scholar Health. The OHRQoL was collected using the Brazilian short version of Child Perceptions Questionnaire 11‐14 (CPQ11‐14). Multilevel Poisson regression models were used to estimate the association between the outcome and the explanatory variables where the adolescents (first level) were nested in their schools (second level).ResultsA total of 768 adolescents were evaluated. Of these, about 15.6% have already used illegal substances. Adolescents who reported the use of illicit substances had 28% higher CPQ11‐14 scores when compared to their counterparts. Alcohol use was also related to worse levels of OHRQoL, while the consumption of cigarettes acted as a protective factor.ConclusionsThis study found an association between the use of alcohol and illicit drugs with worse levels of OHRQoL.